Identification of arsacs mutations and methods of use therefor

ABSTRACT

Isolated spastin genes and fragments thereof, as well as Spastin proteins and fragments thereof are disclosed. Also disclosed are altered forms of spastin, as well as methods for the diagnosis and treatment of neurodegenerative disease.

RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional application Ser. No. 60/160,588, filed Oct. 20, 1999, the entire teachings of which are incorporated herein by reference.

BACKGROUND OF THE INVENTION

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an early-onset neurodegenerative disease with high prevalence in the Charlevoix-Saguenay-Lac-Saint-Jean (CSLSJ) region of Quebec. Disease progression is rapid through young adulthood, with most patients requiring wheelchairs by their early forties. The disease is characterized by abolished sensory nerve conduction, reduced motor nerve velocity, and a unique clinical feature of hypermyelination of retinal nerve fibers. Additional pathological features include atrophy of the upper cerebellar vermis, absence of Purkinje cells, and possibly abnormal neuronal lipid storage (Bouchard, J -P., In: Handbook of Clinical Neurology 16: Hereditary neuropathies and spinocerebellar degenerations, J.M.B.V. de Jong, Ed., pp. 451-459, Elsevier Science Publishers, Amsterdam (1991)). A developmental defect in the myelination of both retinal and peripheral nerve fibers has been proposed as the physiological basis of the disease (Bouchard, J -P., et al., Neuromuscular Disorders 8:474-479 (1998)). More than 300 patients have been identified, and the estimated carrier frequency is 1 in 22 in the Charlevoix-Saguenay-Lac-Saint-Jean (CSLSJ) population of northeastern Quebec (3).

SUMMARY OF THE INVENTION

As described herein, the ARSACS gene, referred to herein as “spastin” (also known as sacsin), has been mapped to chromosome 13q11 by linkage analysis and cloned from human, mouse and hamster. The gene was identified by using fine-structure linkage disequilibrium (LD) mapping to narrow the disease interval and then performing sample-sequencing to identify candidate genes. The spastin gene has a remarkable feature in that it contains a large exon spanning at least 12,793 base pairs of genomic DNA and comprises an open-reading frame of 11,487 base pairs. As described herein the gene is highly conserved in mouse. This exon of spastin is the largest found in any vertebrate organism. The deduced protein contains three large domains with sequence similarity to each other, as well as to the protein predicted to be encoded by an open reading frame identified in Arabidopsis genomic DNA. These domains contain a subdomain with sequence similarity to heat-shock proteins, suggesting a role in chaperone-mediated protein folding. Spastin appears to be expressed in a wide variety of tissues including brain and central nervous system. Alterations in the spastin gene have been identified as described herein which correlate strongly with ARSACS, including at least two alterations which have severe effects on the encoded protein, providing strong evidence that mutations in the open reading frame of the spastin gene are responsible for ARSACS.

The present invention relates to an isolated nucleic acid molecule comprising a spastin gene or portion of said gene as described herein. In one embodiment, the invention relates to an isolated nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of SEQ ID NOS: 1, 3, 7, 9, 11, 12, 13, 14 and 15 and the complement of SEQ ID NOS: 1, 3, 7, 9, 11, 12, 13, 14 and 15. In another embodiment the invention relates to an isolated nucleic acid molecule comprising an exon from a vertebrate gene wherein said exon is at least 1150 base pairs in length. The invention also relates to an isolated nucleic acid molecule consisting of a nucleotide sequence selected from the group consisting of SEQ ID NOS: 1, 3, 7, 9, 11, 12, 13, 14 and 15 and the complement of SEQ ID NOS: 1, 3, 7, 9, 11, 12, 13, 14 and 15. In a preferred embodiment the genes of the invention are human genes. The invention also relates to an isolated nucleic acid molecule consisting of a nucleotide sequence selected from the group consisting of SEQ ID NOS: 21-66 and the complement of SEQ ID NOS: 21-66.

The present invention also includes fragments of the spastin genes described herein. For example, the invention relates to an isolated portion of a nucleic acid sequence selected from the group consisting of SEQ ID NOS: 1, 3, 7, 9, 11, 12, 13, 14 and 15 and the complement of SEQ ID NOS: 1, 3, 7, 9, 11, 12, 13, 14 and 15, wherein the portion is at least about 10 nucleotides in length.

The invention also relates to nucleic acid molecules having substantial sequence identity to the specific sequences disclosed herein. In one embodiment, the invention relates to a nucleic acid molecule comprising a nucleotide sequence which is at least about 60% identical to a nucleotide sequence selected from the group consisting of SEQ ID NOS: 1, 3, 7, 9, 11, 12, 13, 14 and 15 and the complement of SEQ ID NOS: 1, 3, 7, 9, 11, 12, 13, 14 and 15. In another embodiment, the invention relates to a nucleic acid molecule which hybridizes under high stringency conditions to a nucleotide sequence selected from the group consisting of SEQ ID NOS: 1, 3, 7, 9, 11, 12, 13, 14 and 15 and the complement of SEQ ID NOS: 1, 3, 7, 9, 11, 12, 13, 14 and 15.

The nucleic acid molecules of the present invention, or portions thereof, can be used as probes to isolate and/or clone substantially similar or functionally equivalent homologues of the spastin family of genes. The polynucleotides of the present invention can also be used as probes to detect and or measure expression of the genes encoded by the present invention. The probes of the present invention can be DNA, RNA or PNA. Expression assays, such as Southern blot analysis and whole mount in situ hybridization, are well known in the art. The polynucleotides of the present invention, or portions thereof, can also be used as primers to clone homologues or family members by PCR using techniques well known in the art.

The invention further relates to nucleic acid constructs comprising the isolated nucleic acid molecules of the invention, as well as to a recombinant host cell comprising the isolated nucleic acid molecules of the invention. The invention further relates to a method for preparing a polypeptide encoded by an isolated nucleic acid molecule of the invention, comprising culturing the recombinant host cells of the invention.

Also encompassed by the present invention are isolated polypeptides encoded by nucleic acid molecules described herein. For example, the invention relates to an isolated polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NOS: 2, 4, 8, 10, 16 and 67-69. The invention also relates to an isolated polypeptide comprising an amino acid sequence having greater than 75% identity to an amino acid sequence selected from the group consisting of SEQ ID NOS: 2, 4, 8, 10, 16 and 67-69. The invention also provides antibodies, and antigen binding fragments thereof, to the polypeptides of the invention, particularly antibodies and antigen binding fragments thereof which specifically bind the polypeptides described herein.

The invention also provides a method for assaying the presence of a nucleic acid molecule in a sample, comprising contacting said sample with a nucleotide sequence selected from the group consisting of SEQ ID NOS: 1, 3, 7, 9, 11, 12, 13, 14, 15, 17-66, 72 and 73; the complement of SEQ ID NOS: 1, 3, 7, 9, 11, 12, 13, 14, 15, 17-66, 72 and 73; a portion of any one of SEQ ID NOS: 1, 3, 7, 9, 11, 12, 13, 14, 15, 17-66, 72 and 73 which is at least 10 nucleotides in length; and a portion of the complement of any one of SEQ ID NOS: 1, 3, 7, 9, 11, 12, 13, 14, 15, 17-66, 72 and 73 which is at least 10 nucleotides in length, under conditions appropriate for selective hybridization of the sequence to the nucleic acid molecule in the sample. Presence or absence of a hybridization signal indicates presence or absence, respectively, of the target nucleic acid molecule. The invention also relates to a method for assaying the presence of a polypeptide encoded by an isolated nucleic acid molecule of the invention in a sample, comprising contacting said sample with an antibody which specifically binds to the encoded polypeptide.

The invention further relates to a method of diagnosing or aiding in the diagnosis of neurodegenerative disease in an individual comprising obtaining a nucleic acid sample from the individual and determining the nucleotide present at nucleotide position 5254 of SEQ ID NO: 1, wherein the nucleotide position is numbered from the putative initiation codon, wherein presence of a thymine at said position is indicative of increased likelihood of neurodegenerative disease in the individual as compared with an appropriate control, e.g., an individual having a cytosine at said position. The invention also relates to a method of diagnosing or aiding in the diagnosis of neurodegenerative disease in an individual comprising obtaining a nucleic acid sample from the individual and determining whether there is a deletion of a thymine at nucleotide position 6594 of SEQ ID NO: 1, wherein the nucleotide position is numbered from the putative initiation codon, wherein deletion of a thymine at said position is indicative of increased likelihood of neurodegenerative disease in the individual as compared with an appropriate control, e.g., an individual who does not have a deletion at said position.

The invention also relates to a method of treating a neurodegenerative disorder associated with the presence of a thymine at nucleotide position 5254 of SEQ ID NO: 1 in an individual, wherein the nucleotide position is numbered from the putative initiation codon, comprising administering to the individual an agent selected from the group consisting of a polypeptide encoded by SEQ ID NO: 2 or an active portion thereof, a nucleic acid molecule which encodes SEQ ID NO: 2 or an active portion of SEQ ID NO: 2, and an agonist of SEQ ID NO: 2. The invention further relates to a method of treating a neurodegenerative disorder associated with a deletion at nucleotide position 6594 of SEQ ID NO: 1 in an individual, wherein the nucleotide position is numbered from the putative initiation codon, comprising administering to the individual an agent selected from the group consisting of a polypeptide encoded by SEQ ID NO: 2 or an active portion thereof, a nucleic acid molecule which encodes SEQ ID NO: 2 or an active portion of SEQ ID NO: 2, and an agonist of SEQ ID NO: 2.

The invention also encompasses a method of diagnosing or aiding in the diagnosis of neurodegenerative disease associated with the presence of a thymine at nucleotide position 5254 of SEQ ID NO: 1 in an individual, wherein the nucleotide position is numbered from the putative initiation codon, comprising obtaining a sample comprising a Spastin polypeptide from the individual and determining the size of the Spastin polypeptide, wherein if the Spastin polypeptide is significantly shorter than SEQ ID NO: 2 it is indicative of neurodegenerative disease. The invention also provides a method of diagnosing or aiding in the diagnosis of neurodegenerative disease associated with the presence of a deletion at nucleotide position 6594 of SEQ ID NO: 1 in an individual, wherein the nucleotide position is numbered from the putative initiation codon, comprising obtaining a sample comprising a Spastin polypeptide from the individual and determining the size of the Spastin polypeptide, wherein if the Spastin polypeptide is significantly shorter than SEQ ID NO: 2 it is indicative of neurodegenerative disease. In one embodiment, the Spastin polypeptide is significantly shorter than SEQ ID NO: 2 if the Spastin polypeptide comprises less than about 75% of the amino acids of SEQ ID NO: 2.

In one embodiment, the neurodegenerative disease comprises one or more symptoms selected from the group consisting of: reduced sensory nerve conduction, reduced motor nerve velocity, hypermyelination of retinal nerve fibers, atrophy of upper cerebellar vermis, absence of Purkinje cells and abnormal neuronal lipid storage. In a particular embodiment, the nucleic acid sample is obtained from a tissue selected from the group consisting of: brain tissue, CNS, lung, fetal lung, testis, lymphocytes, adipose, fibroblasts, skeletal muscle, pancreas, uterus, kidney, tonsil, embryo and isolated cells thereof. For example, brain tissue can be selected from the group consisting of cerebral cortex, granular cell layer of the cerebellum and hippocampus. In a particular embodiment, the neurodegenerative disease is an early onset neurodegenerative disease.

BRIEF DESCRIPTION OF TEE DRAWINGS

FIG. 1 is a schematic diagram of the structure and organization of the spastin gene. Markers used for the genetic map of the spastin gene are shown above. SGCG is the sarcoglycan, gamma gene. hCIT 26_L₁₃ 1 and hCIT 235_L_(—)20, the overlapping clones that contain the spastin ORF, are 110 kilobases (kb) and 60 kb, respectively. Exploded view shows the location of the spastin gene. The thick bar is the predicted coding region. The thin bars represent the 5′ and 3′ UTRs. M is the first methionine. S is the location fo the introduced stop codon found on the minor haplotype. Δ indicates the location of the deleted base pair found on the major haplotype. AB018273 is the mRNA sequence KIAA0730 (42) which is part of a UniGene cluster (Hs.159492) containing 32 ESTs. R17106, AA776169, AA776670, and AA897178 are additional ESTs with homology to the spastin gene.

FIGS. 2A-2B show the results of sequence analysis and identification of spastin mutations found on ARSACS chromosomes. The sequences displayed are from direct sequencing of PCR products and flank the two mutations (indicated by arrows) found on ARSACS chromosomes. Nucleotide numbering is from the putative initiation codon. FIG. 2A shows nucleotide 6594 (codon 2198) for an unaffected individual (top panel) and a homozygous affected individual (bottom panel). FIG. 2B shows nucleotide 5254 (codon 1752) for an unaffected individual (top panel) and an affected compound heterozygous individual (bottom panel).

FIG. 3 shows a Northern blot analysis of spastin mRNA. A ³²P-labelled 1.8 kb cDNA fragment from the 3′ end of the spastin gene (Image clone #279258) was hybridized to a blot of fibroblast RNA and to a multiple tissue blot (MTN, Clontech). Lanes 1-5 contain patient fibroblast RNAs and lane 6 contains control fibroblast RNA. The lanes of the MTN blot correspond to the following tissues: 7, heart; 8, brain; 9, placenta; 10, lung; 11, liver; 12, skeletal muscle; 13, kidney; and 14, pancreas. The marker (M) is the 0.24-9.5 kb RNA ladder (Life Technologies).

FIGS. 4A-4B are schematic representations of the Spastin protein and relevant homologies. FIG. 4A shows a schematic representation of the Spastin protein and location of motifs. rep. 1, 2, and 3 represent the domains with homology (28, 30 and 21% identity, respectively) to the Arabidopsis open reading frame. FIG. 4B shows homology between the two Hsp90 domains of Spastin, the first mouse domain, the Arabidopsis open reading frame (GenBank accession #AB006708), and the yeast Hsp90 (GenBank accession #3401959). Alignment was performed with ClustalW (1.7)(43) through the BCM Search Launcher interface (34) with the BLOSUM weight matrix. The numbering for all sequences is from the first methionine (nucleotide 50,773 is the first methionine of the Arabidopsis open reading frame).

FIGS. 5A-5C show the alignment of the human Spastin with the mouse Spastin. Identical amino acids and gaps are represented by dots and hyphens, respectively. The self-homologous region containing the Hsp90 homology occurs at positions 705-833 and 1773-1895, and italics indicate the DnaJ region. The bolded sequences represent leucine zipper motifs, underlined sequences represent coiled coil domains, and the boxed and underlined sequence delineates the putative hydrophilic region. The first coiled coil domain is interrupted by a proline in the mouse sequence.

FIG. 6 is a table showing ESTs identified by sample-sequencing of the ARSACS critical interval.

FIG. 7 is a table showing primers for PCR amplification of the human spastin gene.

FIGS. 8A-8G show the complete exon (SEQ ID NO: 3) of the murine spastin gene as shown in FIGS. 8A-8G.

FIGS. 9A-9F show the complete exon (SEQ ID NO: 1) of the human spastin gene.

DETAILED DESCRIPTION OF THE INVENTION

The gene responsible for ARSACS was mapped to chromosome region 13q11 by genotyping 322 microsatellite markers in a genome-wide scan and noting a high degree of homozygosity at locus D13S787 (Bouchard, J -P., et al., Neuromuscular Disorders 8:474-479 (1998)). Extensive genetic analysis of the region defined a maximum multi-point LOD score of 42.3 and revealed a major conserved haplotype among ARSACS chromosomes in a 11.1 cM region flanked by D13S1236 and D13S1285 (5). Two groups of ARSACS haplotypes were found between D13SJ275 and D13S292. The overwhelming majority (96%) of ARSACS chromosomes carried a single haplotype, defined by D13S232 and two single nucleotide polymorphisms (SNPs) within the sarcoglycan, gamma gene (SGCG). Location score analysis demonstrated that the most likely position of the ARSACS was between D13S232 and D13S292 (the critical interval)(5).

A high-resolution physical and transcript map of the ARSACS critical interval was constructed in yeast artificial chromosomes (YACs), bacterial artificial chromosomes (BACs) and plasmid artificial chromosomes (PACs). The identification of the ARSACS gene (i.e., a gene in which alteration is associated with ARSACS) was carried out as described herein by performing sample-sequencing of six BAC and PAC clones spanning about 450 kilobases (kb) included in the critical interval. Analysis of the sample sequences revealed human ESTs (FIG. 6) and the presence of two known genes: sodium/potassium-ATPase (ATP1AL1), that was excluded on the basis of recombination in ARSACS families, and SGCG, a gene in which no sequence variants unique to ARSACS chromosomes were found.

A 20 kb sequence contig revealed a huge genomic open reading frame (ORF) of 11,487-base pairs that encodes 3829 amino acids (SEQ ID NO: 2). The open reading frame (ORF) begins with an AUG codon preceded by an in-frame stop codon 75 bp upstream and continues for a total of 3,829 codons before encountering a stop codon. One large cDNA (KIAA0730) derived from a brain library and over 30 ESTs overlap the ORF and allowed the determination of the 3′ untranslated region (UTR), which extends 1,307 bp to a polyadenylation site (FIG. 1). The existence of this gigantic exon was confirmed by analyzing RT-PCR products spanning the entire mRNA; this analysis showed perfect correspondence between the mRNA and genomic DNA sequence. Thus, the total length of the exon must be at least 12,793 bp. A probe derived from within this sequence detects a transcript of approximately 12.8 kb on a Northern blot, suggesting that the identified exonic sequence may constitute an intronless gene, although the possibility of a small 5′ exon cannot be excluded.

To characterize the full sequence of the ORF and to identify potential disease-causing mutations, PCR products from ARSACS patient and control DNA were sequenced. The primers for these reactions are shown in FIG. 7. A single-base deletion of a thymine at position 6594 (6594ΔT) (FIG. 2A), wherein the nucleotide position is numbered from the putative initiation codon, was found on all copies of the major ancestral haplotype examined (a total of 32 chromosomes), but was absent in all chromosomes of carrier parents that were not transmitted to ARSACS offspring. This mutation causes a frame shift and results in a subsequent stop codon that truncates the final 43% of the predicted protein. A second mutation, a nonsense mutation of substitution of a thymine for a cytosine at nucleotide position 5254 (c5254T) (FIG. 2B), wherein the nucleotide position is numbered from the putative initiation codon results in the substitution of a stop codon for an arginine and was found on the minor ARSACS haplotype carried in a heterozygous state (in trans to the major ARSACS mutation) in six patients from two families (5). Both mutations are thus completely associated with their respective core haplotypes and are predicted to have severe effects on the encoded protein. The presence of these two mutations provides strong evidence that mutations in this ORF are responsible for ARSACS. The gene is referred to herein as spastin (gene symbol: SPAS).

In the course of the complete resequencing of the spastin gene in ARSACS patients, additional sequence variants were found which proved to be polymorphisms found on non-ARSACS-bearing chromosomes as well. These included four silent substitutions: substitution of a thymine for a cytosine at nucleotide position 3945, substitution of a cytosine for a thymine at nucleotide position 6603, substitution of a thymine for a cytosine at nucleotide position 7731, and substitution of a thymine for a cytosine at nucleotide position 10054 (C3945T, T6603C, C7731T and C10054T, respectively), and an amino acid-altering substitution of a cytosine for a thymine at nucleotide position 7856 (T7856C), wherein the nucleotide position is numbered from the putative initiation codon, that results in the substitution of an alanine for a valine in the predicted protein.

Spastin mRNA was detected by northern blot analysis in fibroblasts, brain and skeletal muscle (FIG. 3, lanes 1-6, 8 and 12) and at very low levels in pancreas (FIG. 3, lane 14). A single transcript of roughly 12.8 kb was seen in all cases. Spastin mRNA was expressed in the fibroblasts of ARSACS patients (FIG. 3, lanes 1-5) at the same size as controls, which is not unexpected because both mutations alter only a single nucleotide.

To examine the tissue expression pattern of spastin more closely, in situ hybridizations were performed. Human, monkey, and rat brain all demonstrated high levels of staining, which included all layers of the cerebral cortex and the granular cell layer of the cerebellum. In a sagittal section of the adult rat brain, strong labeling was seen in most if not all areas of the central nervous system (CNS). Particularly intense labeling was observed on the hippocampus. No labeling is seen with the sense probe. In addition, specific staining of spastin mRNA was seen throughout the CNS of the 18-19 day fetal rat. Background staining with the sense probe does not include the CNS. Spastin ESTs were identified from the cDNA libraries of many tissues including brain, uterus, kidney, tonsils, liver, and T cells. Transcripts from brain and multiple sclerosis libraries comprise 13 of the 35 human ESTs with homology to spastin. Taken together, these lines of evidence indicate that spastin is expressed in a variety of tissues, including many that are neural-derived.

On the basis of its amino acid sequence, the Spastin protein product is predicted to have a molecular weight of 437 kD and a pI of 6.85. Structure prediction programs suggest the presence of two leucine zippers, three coiled coils and a hydrophilic domain, all within the C-terminal half of the protein (FIGS. 4A and 5A-5C). The predicted protein product does not show extensive similarity to any known protein, based on analyses using a variety of different sequence comparison tools. However, two related motifs were identified. The C-terminal portion of the predicted protein contains a ‘DnaJ’ protein motif (FIGS. 4A and 5A-5C, residues 3574-3590). Both human and mouse proteins also contain three large segments with sequence similarity to each other, of which two have homology to the N-terminal domain of the Hsp90 class of heat-shock proteins from a variety of organisms. These Hsp90 subdomains are found in spastin residues 705-833 and 1773-1895 (FIGS. 4A and 5A-5C). As discussed below, the DnaJ and Hsp90 protein classes are both involved in molecular chaperone complexes. Interestingly, the three large segments also show strong similarity to a BAC clone recently sequenced as part of the Arabidopsis genome project (GenBank #AB006708). Specifically, they are homologous to a portion of a 5,871 bp ORF of unknown function in Arabidopsis (FIG. 5A). An alignment of the Hsp90 domain is shown for the first and second large segments from human, the first segment for mouse, the Arabidopsis ORF and the yeast Hsp90 (FIG. 5B). The highly conserved residues correspond to regions already identified as highly conserved “signature sequences” in an extensive phylogenetic analysis of the Hsp90 family (9). Molecular chaperones are known to function in multiple sub-cellular compartments. A knowledge-based program for predicted subcellular localization, PSORT II (10) favored a nuclear localization for the Spastin protein, but the prediction score was relatively weak (47%).

As provided herein, the spastin gene is also conserved in mouse. Homologous mouse ESTs were identified, including one having a polyadenylation signal. Using these ESTs to screen a mouse BAC library (CitbCJ7), the mouse spastin gene was isolated, identified and sequenced. Sequence analysis of the mouse spastin genomic clone revealed the presence of a huge ORF, which is three nucleotides longer than the human homologue and thus, the mouse Spastin protein is predicted to be one amino acid longer. The entire ORF is well conserved between mouse and human, both at the DNA level (88% homology) and at the protein level (94% identity, 97% similarity). The areas of high sequence conservation between mouse and human included the two leucine zippers, two coiled coils, the Hsp90 and DnaJ domains, and the repeated Arabidopsis ORF homology (FIGS. 5A-5C). The 3′ UTRs show greater divergence between the mouse and human, but still retain 72% homology. The mouse spastin gene was mapped to chromosome 1, near D1Mit373, on the basis of radiation hybrid mapping (LOD score of 25.5) using the Whitehead Institute mouse T31 RH framework (11, 12).

Work described herein strongly supports that a frameshift and a nonsense mutation identified within the spastin gene cause ARSACS. Though the gene appears to be widely expressed, the truncation of the Spastin protein caused either by homozygous (6594ΔT/6594ΔT) or compound heterozygous (C5254T/6594ΔT) genotypes, wherein the nucleotide position is numbered from the putative initiation codon, apparently lead to symptoms predominantly affecting the nervous system. The high level of expression of spastin mRNA in the granular cell layer of the adult rat cerebellum is especially interesting in light of an earlier observation of the reduced thickness of the granular layer found during the postmortem examination of tissue from an ARSACS patient (Bouchard, J -P., In: Handbook of Clinical Neurology 16: hereditary neuropathies and spinocerebellar degenerations, pp.451-459, Elsevier Science Publishers, Amsterdam (1991)). Thus, the high mRNA expression levels seen in the CNS indicate a possibly unique role for Spastin in the genesis or maintenance of neural cell function.

As described herein, sample-sequencing of the ARSACS critical region, in combination with directed sequencing of specific subclones and computer-aided analysis led to the characterization of a very large exon directly from genomic DNA. This likely represents the entire coding sequence of the spastin gene as the first methionine is preceded by an in-frame stop codon 75 bp upstream. RT-PCR demonstrated that the sequence, from this 75 bp until the polyadenylation site, is transcribed. Spastin appears to be an intronless gene, although a non-coding upstream exon cannot be ruled out. The spastin exon of at least 12,793 bp encoding an ORF of 11,487 bp represents the largest exon and the largest ORF within an exon found in any vertebrate so far. The next largest exons reported are the X (inactive)-specific transcript (XIST) (11,363 bp) which does not code for a protein (13), and the large central exon of the mucin gene (MUC5B) which is 10,713 bp long (14).

Intronless ORFs are uncommon and thought to represent at most 5% of human genes. A few gene families are frequently intronless, including histones and G-protein-coupled receptors (GPCRs) (15). Members of the Hsp70 family, but not the Hsp90, are also intronless. The strong conservation between both the human and the mouse spastic and the unusually large 5,871 bp Arabidopsis ORF suggest both that spastin is ancient and that the large size of the exon is functionally important.

The presence of similarities to DnaJ and Hsp90 proteins sheds light on spastin's potential function. Examples of interacting protein pairs having homologues of the two proteins fused into a single protein are well known in the art (17). Spastin possesses both the N-terminal domain of the Hsp90 protein class and a DnaJ domain. These two domains are from proteins that interact in chaperone-mediated protein folding. The DnaJ motif has long been known to form heterocomplexes with the Hsp70 class of proteins in a variety of cellular processes, including ATP-dependent folding of target proteins. The N-terminal domain of the Hsp90 protein class contains an ATP-binding site that is very similar to the one found in DNA gyrase B (18). More recently, it has been shown that the yeast DNAJ homologue, YDJ1, physically associates with Hsp90 and this interaction has specific effects on Hsp90 substrates (19). In addition, other studies have shown that a rabbit DnaJ homologue (p40) interacts with Hsp70 and Hsp90 (both molecular chaperones) to form heterocomplexes known as “foldosomes” (20). Together, these data suggest that spastin functions in chaperone-mediated protein folding.

As described herein the mouse spastin gene was mapped to chromosome 1 near D1Mit373. A recessive mouse mutation known as tumbler (tb: MGI Accession ID:98489) was previously mapped to this region by linkage (21). Tumbler mice had an ataxia that caused them to “walk in a crab-like fashion.” They somersaulted, fell over, or jumped when trying to go forward. Most of the homozygotes survived and bred (21). These observations are similar to those seen in ARSACS patients whose life expectancy, although reduced (mean age at death is 51 years) still permits some to survive until the eighth decade. The fertility of affected females seems unchanged, but because overall nuptiality is low, male fertility has been difficult to assess (Bouchard, J -P., et al., Nueromuscular Disorders 8:474-479 (1998)). Unfortunately, the tb mouse line has died out (Mouse Genome Database: URL:http://www.informatics.jax.org/). However, gene knock-out of the mouse spastin gene could serve to confirm that the tb mutation was a mutation in the mouse spastin gene.

SEQ ID NOS: referred to herein are as follows. SEQ ID NO: 1 refers to the complete exon of the human spastin gene as shown in FIGS. 9A-9F. SEQ ID NO: 2 refers to the protein encoded by the ORF of SEQ ID NO: 1, particularly as shown in FIGS. 9A-9F and 5A-5C. SEQ ID NO: 3 refers to the complete exon of the murine spastin gene as shown in FIGS. 8A-8G. SEQ ID NO: 4 refers to the protein encoded by the ORF of SEQ ID NO: 3, particularly as shown in FIGS. 9A-9F and 5A-5C. SEQ ID NOS: 5 and 6 are intentionally omitted. SEQ ID NO: 7 refers to a nucleotide sequence which is identical to SEQ ID NO: 1 except for a deletion of a thymine at position 6594, wherein the nucleotide position is numbered from the putative initiation codon. SEQ ID NO: 8 refers to the protein encoded by the ORF of SEQ ID NO: 7. SEQ ID NO: 9 refers to a nucleotide sequence which is identical to SEQ ID NO: 1 except for a substitution of a thymine for a cytosine at position 5254, wherein the nucleotide position is numbered from the putative initiation codon. SEQ ID NO: 10 refers to the protein encoded by the ORF of SEQ ID NO: 9. SEQ ID NO: 11, 12, 13 and 14 refer to nucleotide sequences which are identical to SEQ ID NO: 1 except for a substitution of a thymine for a cytosine at position 3945, substitution of a cytosine for a thymine at position 6603, substitution of a thymine for a cytosine at position 7731, and substitution of a thymine for a cytosine at position 10054, wherein the nucleotide position is numbered from the putative initiation codon, respectively. SEQ ID NO: 15 refers to a nucleotide sequence which is identical to SEQ ID NO: 1 except for substitution of a cytosine for a thymine at position 7856, wherein the nucleotide position is numbered from the putative initiation codon. SEQ ID NO: 16 refers to the protein encoded by the ORF of SEQ ID NO: 15. The sequences corresponding to all other SEQ ID NOS: used herein are shown throughout the application.

As appropriate, the isolated nucleic acid molecules of the present invention can be RNA, for example, mRNA, or DNA, such as cDNA and genomic DNA. DNA molecules can be double-stranded or single-stranded; single stranded RNA or DNA can be either the coding, or sense, strand or the non-coding, or antisense, strand. The nucleic acid molecule can include all or a portion of the coding sequence of a gene and can further comprise additional non-coding sequences such as introns and non-coding 3′ and 5′ sequences (including regulatory sequences, for example). Additionally, the nucleic acid molecule can be fused to a marker sequence, for example, a sequence that encodes a polypeptide to assist in isolation or purification of the polypeptide. Such sequences include, but are not limited to, those which encode a glutathione-S-transferase (GST) fusion protein and those which encode a hemaglutin A (HA) polypeptide marker from influenza.

As used herein, “isolated” is intended to mean that the isolated item is not in the form or environment in which it exists in nature. For example, an “isolated” nucleic acid molecule, as used herein, is one that is separated from nucleic acid which normally flanks the nucleic acid molecule in nature. With regard to genomic DNA, the term “isolated” refers to nucleic acid molecules which are separated from the chromosome with which the genomic DNA is naturally associated. For example, the isolated nucleic acid molecule can contain less than about 5 kb, 4 kb, 3 kb, 2 kb, 1 kb, 0.5 kb or 0.1 kb of nucleotides which flank the nucleic acid molecule in the genomic DNA of the cell from which the nucleic acid is derived.

Moreover, an isolated nucleic acid of the invention, such as a cDNA or RNA molecule, can be substantially free of other cellular material, or culture medium when produced by recombinant techniques, or chemical precursors or other chemicals when chemically synthesized. However, the nucleic acid molecule can be fused to other coding or regulatory sequences and still be considered isolated. In some instances, the isolated material will form part of a composition (for example, a crude extract containing other substances), buffer system or reagent mix. In other circumstances, the material may be purified to essential homogeneity, for example as determined by PAGE or column chromatography such as HPLC. Preferably, an isolated nucleic acid comprises at least about 50, 80 or 90% (on a molar basis) of all macromolecular species present.

Further, recombinant DNA contained in a vector is included in the definition of “isolated” as used herein. Also, isolated nucleic acid molecules include recombinant DNA molecules in heterologous host cells, as well as partially or substantially purified DNA molecules in solution. “Isolated” nucleic acid molecules also encompass in vivo and in vitro RNA transcripts of the DNA molecules of the present invention.

The invention further provides variants of the isolated nucleic acid molecules of the invention. Such variants can be naturally occurring, such as allelic variants (same locus), homologs (different locus), and orthologs (different organism), or may be constructed by recombinant DNA methods or by chemical synthesis. Such non-naturally occurring variants can be made using well-known mutagenesis techniques, including those applied to polynucleotides, cells, or organisms. Accordingly, variants can contain nucleotide substitutions, deletions, inversions and/or insertions in either or both the coding and non-coding region of the nucleic acid molecule. Further, the variations can produce both conservative and non-conservative amino acid substitutions.

Typically, variants have a substantial identity with a nucleic acid molecule disclosed herein and the complements thereof. Particularly preferred are nucleic acid molecules and fragments which have at least about 60%, preferably at least about 70, 80 or 85%, more preferably at least about 90%, even more preferably at least about 95%, and most preferably at least about 98% identity with nucleic acid molecules described herein.

Such nucleic acid molecules can be readily identified as being able to hybridize under stringent conditions to a nucleotide sequence selected from the group consisting of SEQ ID NOS: 1, 3, 7, 9, 11, 12, 13, 14, 15, 17-66, 72 and 73 and the complements thereof. In one embodiment, the variants hybridize under high stringency hybridization conditions (e.g., for selective hybridization) to a nucleotide sequence selected from SEQ ID NOS:1, 3, 7, 9, 11, 12, 13, 14, 15, 17-66, 72 and 73.

A general description of stringent hybridization conditions are discussed in Ausubel, F. M., et al., Current Protocols in Molecular Biology, Greene Publishing Assoc. and Wiley-Interscience 1989, the teachings of which are incorporated herein by reference. Factors such as probe length, base composition, percent mismatch between the hybridizing sequences, temperature and ionic strength influence the stability of nucleic acid hybrids. Thus, stringency conditions sufficient to identify the polynucleotides of the present invention, (e.g., high or moderate stringency conditions) can be determined empirically, depending in part upon the characteristics of the known DNA to which other unknown nucleic acids are being compared for sequence similarity. Equivalent conditions can be determined by varying one or more of these parameters while maintaining a similar degree of identity or similarity between the two nucleic acid molecules. Typically, conditions are used such that sequences at least about 60%, at least about 70%, at least about 80%, at least about 90% or at least about 95% or more identical to each other remain hybridized to one another.

Alternatively, conditions for stringency are as described in WO 98/40404, the teachings of which are incorporated herein by reference. In particular, examples of highly stringent, stringent, reduced and least stringent conditions are provided in WO 98/40404 in the Table on page 36. In one embodiment, highly stringent conditions are those that are at least as stringent as, for example, 1× SSC at 65° C., or 1× SSC and 50% formamide at 42° C. Moderate stringency conditions are those that are at least as stringent as 4× SSC at 65° C., or 4× SSC and 50% formamide at 42° C. Reduced stringency conditions are those that are at least as stringent as 4× SSC at 50° C., or 6× SSC and 50% formamide at 40° C.

The percent identity of two nucleotide or amino acid sequences can be determined by aligning the sequences for optimal comparison purposes (e.g., gaps can be introduced in the sequence of a first sequence). The nucleotides or amino acids at corresponding positions are then compared, and the percent identity between the two sequences is a function of the number of identical positions shared by the sequences (i.e., % identity # of identical positions/total # of positions×100). In certain embodiments, the length of a sequence aligned for comparison purposes is at least 30%, preferably at least 40%, more preferably at least 60%, and even more preferably at least 70%, 80% or 90% of the length of the reference sequence. The actual comparison of the two sequences can be accomplished by well-known methods, for example, using a mathematical algorithm. A preferred, non-limiting example of such a mathematical algorithm is described in Karlin et al., Proc. Natl. Acad. Sci. USA, 90:5873-5877 (1993). Such an algorithm is incorporated into the NBLAST and XBLAST programs (version 2.0) as described in Altschul et al., Nucleic Acids Res., 25:389-3402 (1997). When utilizing BLAST and Gapped BLAST programs, the default parameters of the respective programs (e.g., NBLAST) can be used. See http://www.ncbi.nlm.nih.gov. In one embodiment, parameters for sequence comparison can be set at score=100, wordlength=12, or can be varied (e.g., W=5 or W=20).

The present invention also provides isolated nucleic acids that contain a fragment or portion that hybridizes under highly stringent conditions to a nucleotide sequence selected from the group consisting of SEQ ID NOS: 1, 3, 7, 9, 11, 12, 13, 14, 15, 17-66, 72 and 73 described herein and the complements of these SEQ ID NOS. The nucleic acid fragments of the invention are at least about 15, preferably at least about 18, 20, 23 or 25 nucleotides, and can be 30, 40, 50, 100, 200 or more nucleotides in length. Longer fragments, for example, 30 or more nucleotides in length, which encode antigenic proteins or polypeptides described herein are useful.

In a related aspect, the nucleic acid fragments of the invention are used as probes or primers in assays such as those described herein. “Probes” are oligonucleotides that hybridize in a base-specific manner to a complementary strand of nucleic acid. Such probes include polypeptide nucleic acids, as described in Nielsen et al., Science, 254, 1497-1500 (1991). Typically, a probe comprises a region of nucleotide sequence that hybridizes under highly stringent conditions to at least about 15, typically about 20-25, and more typically about 40, 50 or 75 consecutive nucleotides of a nucleic acid molecule of the invention. More typically, the probe further comprises a label, e.g., radioisotope, fluorescent compound, enzyme, or enzyme co-factor.

As used herein, the term “primer” refers to a single-stranded oligonucleotide which acts as a point of initiation of template-directed DNA synthesis using well-known methods (e.g., PCR, LCR) including, but not limited to those described herein. The appropriate length of the primer depends on the particular use, but typically ranges from about 15 to 30 nucleotides. The term “primer site” refers to the area of the target DNA to which a primer hybridizes. The term “primer pair” refers to a set of primers including a 5′ (upstream) primer that hybridizes with the 5′ end of the nucleic acid sequence to be amplified and a 3′ (downstream) primer that hybridizes with the complement of the sequence to be amplified.

The nucleic acid molecules of the invention such as those described above can be identified and isolated using standard molecular biology techniques and the sequence information provided herein. For example, nucleic acid molecules can be amplified and isolated by the polymerase chain reaction using synthetic oligonucleotide primers designed based on one or more of the sequences provided herein and the complements thereof. See generally PCR Technology: Principles and Applications for DNA Amplification (ed. H. A. Erlich, Freeman Press, NY, N.Y., 1992); PCR Protocols: A Guide to Methods and Applications (Eds. Innis, et al., Academic Press, San Diego, Calif., 1990); Mattila et al., Nucleic Acids Res., 19:4967 (1991); Eckert et al., PCR Methods and Applications, 1:17 (1991); PCR (eds. McPherson et al., IRL Press, Oxford); and U.S. Pat. No. 4,683,202. The nucleic acid molecules can be amplified using cDNA, mRNA or genomic DNA as a template, cloned into an appropriate vector and characterized by DNA sequence analysis.

Other suitable amplification methods include the ligase chain reaction (LCR) (see Wu and Wallace, Genomics, 4:560 (1989), Landegren et al., Science, 241:1077 (1988), transcription amplification (Kwoh et al., Proc. Natl. Acad. Sci. USA, 86:1173 (1989)), and self-sustained sequence replication (Guatelli et al., Proc. Nat. Acad. Sci. USA, 87:1874 (1990)) and nucleic acid based sequence amplification (NASBA). The latter two amplification methods involve isothermal reactions based on isothermal transcription, which produce both single stranded RNA (ssRNA) and double stranded DNA (dsDNA) as the amplification products in a ratio of about 30 or 100 to 1, respectively.

For example, the amplified DNA can be radiolabelled and used as a probe for screening a cDNA library derived from fibroblast or brain, e.g., human fibroblast or brain, mRNA in zap express, ZIPLOX or other suitable vector. Corresponding clones can be isolated, DNA can obtained following in vivo excision, and the cloned insert can be sequenced in either or both orientations by art recognized methods to identify the correct reading frame encoding a protein of the appropriate molecular weight. For example, the direct analysis of the nucleotide sequence of nucleic acid molecules of the present invention can be accomplished using well-known methods that are commercially available. See, for example, Sambrook et al., Molecular Cloning, A Laboratory Manual (2nd Ed., CSHP, New York 1989); Zyskind et al., Recombinant DNA Laboratory Manual, (Acad. Press, 1988)). Using these or similar methods, the protein(s) and the DNA encoding the protein can be isolated, sequenced and further characterized.

Antisense nucleic acids of the invention can be designed using the nucleotide sequences described herein, and constructed using chemical synthesis and enzymatic ligation reactions using procedures known in the art. For example, an antisense nucleic acid (e.g., an antisense oligonucleotide) can be chemically synthesized using naturally occurring nucleotides or variously modified nucleotides designed to increase the biological stability of the molecules or to increase the physical stability of the duplex formed between the antisense and sense nucleic acids, e.g., phosphorothioate derivatives and acridine substituted nucleotides can be used.

In general, the isolated nucleic acid sequences can be used as molecular weight markers on Southern gels, and as chromosome markers which are labeled to map related gene positions. The nucleic acid sequences can also be used to compare with endogenous DNA sequences in patients to identify genetic disorders, and as probes, such as to hybridize and discover related DNA sequences or to subtract out known sequences from a sample. The nucleic acid sequences can further be used to derive primers for genetic fingerprinting, to raise anti-protein antibodies using DNA immunization techniques, and as an antigen to raise anti-DNA antibodies or elicit immune responses. Additionally, the nucleotide sequences of the invention can be used identify and express recombinant proteins for analysis, characterization or therapeutic use, or as markers for tissues in which the corresponding protein is expressed, either constitutively, during tissue differentiation, or in diseased states.

The invention also relates to constructs which comprise a vector into which a sequence of the invention has been inserted in a sense or antisense orientation. As used herein, the term “vector” refers to a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked. One type of vector is a “plasmid”, which refers to a circular double stranded DNA loop into which additional DNA segments can be ligated. Another type of vector is a viral vector, wherein additional DNA segments can be ligated into the viral genome. Certain vectors are capable of autonomous replication in a host cell into which they are introduced (e.g., bacterial vectors having a bacterial origin of replication and episomal mammalian vectors). Other vectors (e.g., non-episomal mammalian vectors) are integrated into the genome of a host cell upon introduction into the host cell, and thereby are replicated along with the host genome. Moreover, certain vectors, expression vectors, are capable of directing the expression of genes to which they are operably linked. In general, expression vectors of utility in recombinant DNA techniques are often in the form of plasmids (vectors). However, the invention is intended to include such other forms of expression vectors, such as viral vectors (e.g., replication defective retroviruses, adenoviruses and adeno-associated viruses) that serve equivalent functions.

Preferred recombinant expression vectors of the invention comprise a nucleic acid of the invention in a form suitable for expression of the nucleic acid in a host cell. This means that the recombinant expression vectors include one or more regulatory sequences, selected on the basis of the host cells to be used for expression, which is operably linked to the nucleic acid sequence to be expressed. Within a recombinant expression vector, “operably linked” is intended to mean that the nucleotide sequence of interest is linked to the regulatory sequence(s) in a manner which allows for expression of the nucleotide sequence (e.g., in an in vitro transcription/translation system or in a host cell when the vector is introduced into the host cell). The term “regulatory sequence” is intended to include promoters, enhancers and other expression control elements (e.g., polyadenylation signals). Such regulatory sequences are described, for example, in Goeddel, Gene Expression Technology: Methods in Enzymology 185, Academic Press, San Diego, Calif. (1990). Regulatory sequences include those which direct constitutive expression of a nucleotide sequence in many types of host cell and those which direct expression of the nucleotide sequence only in certain host cells (e.g., tissue-specific regulatory sequences). It will be appreciated by those skilled in the art that the design of the expression vector can depend on such factors as the choice of the host cell to be transformed, the level of expression of protein desired, etc.

The expression vectors of the invention can be introduced into host cells to thereby produce proteins or peptides, including fusion proteins or peptides, encoded by nucleic acids as described herein. The recombinant expression vectors of the invention can be designed for expression of a polypeptide of the invention in prokaryotic or eukaryotic cells, e.g., bacterial cells such as E. coli, insect cells (using baculovirus expression vectors), yeast cells or mammalian cells. Suitable host cells are discussed further in Goeddel, supra. Alternatively, the recombinant expression vector can be transcribed and translated in vitro, for example using T7 promoter regulatory sequences and T7 polymerase.

Another aspect of the invention pertains to host cells into which a recombinant expression vector of the invention has been introduced. The terms “host cell” and “recombinant host cell” are used interchangeably herein. It is understood that such terms refer not only to the particular subject cell but also to the progeny or potential progeny of such a cell. Because certain modifications may occur in succeeding generations due to either mutation or environmental influences, such progeny may not, in fact, be identical to the parent cell, but are still included within the scope of the term as used herein.

A host cell can be any prokaryotic or eukaryotic cell. For example, a nucleic acid of the invention can be expressed in bacterial cells (e.g. E. coli), insect cells, yeast or mammalian cells (such as Chinese hamster ovary cells (CHO) or COS cells). Other suitable host cells are known to those skilled in the art.

Vector DNA can be introduced into prokaryotic or eukaryotic cells via conventional transformation or transfection techniques. As used herein, the terms “transformation” and “transfection” are intended to refer to a variety of art-recognized techniques for introducing foreign nucleic acid (e.g., DNA) into a host cell, including calcium phosphate or calcium chloride co-precipitation, DEAE-dextran-mediated transfection, lipofection, or electroporation. Suitable methods for transforming or transfecting host cells can be found in Sambrook, et al. (supra), and other laboratory manuals.

A host cell of the invention, such as a prokaryotic or eukaryotic host cell in culture, can be used to produce (i.e., express) a polypeptide of the invention. Accordingly, the invention further provides methods for producing a polypeptide using the host cells of the invention. In one embodiment, the method comprises culturing the host cell of invention (into which a recombinant expression vector encoding a polypeptide of the invention has been introduced) in a suitable medium such that the polypeptide is produced. In another embodiment, the method further comprises isolating the polypeptide from the medium or the host cell.

The host cells of the invention can also be used to produce nonhuman transgenic animals. For example, in one embodiment, a host cell of the invention is a fertilized oocyte or an embryonic stem cell into which a nucleic acid of the invention have been introduced. Such host cells can then be used to create non-human transgenic animals in which exogenous nucleotide sequences have been introduced into their genome or homologous recombinant animals in which endogenous nucleotide sequences have been altered. Such animals are useful for studying the function and/or activity of the nucleotide sequence and polypeptide encoded by the sequence and for identifying and/or evaluating modulators of their activity. As used herein, a “transgenic animal” is a non-human animal, preferably a mammal, more preferably a rodent such as a rat or mouse, in which one or more of the cells of the animal includes a transgene. Other examples of transgenic animals include non-human primates, sheep, dogs, cows, goats, chickens, amphibians, etc. A transgene is exogenous DNA which is integrated into the genome of a cell from which a transgenic animal develops and which remains in the genome of the mature animal, thereby directing the expression of an encoded gene product in one or more cell types or tissues of the transgenic animal. As used herein, an “homologous recombinant animal” is a non-human animal, preferably a mammal, more preferably a mouse, in which an endogenous gene has been altered by homologous recombination between the endogenous gene and an exogenous DNA molecule introduced into a cell of the animal, e.g., an embryonic cell of the animal, prior to development of the animal.

A transgenic animal of the invention can be created by introducing a nucleic acid of the invention into the male pronuclei of a fertilized oocyte, e.g., by microinjection, retroviral infection, and allowing the oocyte to develop in a pseudopregnant female foster animal. The sequence can be introduced as a transgene into the genome of a non-human animal. Intronic sequences and polyadenylation signals can also be included in the transgene to increase the efficiency of expression of the transgene. A tissue-specific regulatory sequence(s) can be operably linked to the transgene to direct expression of a polypeptide in particular cells. Methods for generating transgenic animals via embryo manipulation and microinjection, particularly animals such as mice, have become conventional in the art and are described, for example, in U.S. Pat. Nos. 4,736,866 and 4,870,009, U.S. Pat. No. 4,873,191 and in Hogan, Manipulating the Mouse Embryo (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1986). Similar methods are used for production of other transgenic animals. A transgenic founder animal can be identified based upon the presence of the transgene in its genome and/or expression of mRNA in tissues or cells of the animals. A transgenic founder animal can then be used to breed additional animals carrying the transgene. Moreover, transgenic animals carrying a transgene encoding the transgene can further be bred to other transgenic animals carrying other transgenes.

The present invention also provides isolated polypeptides and variants and fragments thereof that are encoded by the nucleic acid molecules of the invention. For example, as described above, the nucleotide sequences can be used to design primers to clone and express cDNAs encoding the polypeptides of the invention.

As used herein, a polypeptide is said to be “isolated” or “purified” when it is substantially free of cellular material when it is isolated from recombinant and non-recombinant cells, or free of chemical precursors or other chemicals when it is chemically synthesized. A polypeptide, however, can be joined to another polypeptide with which it is not normally associated in a cell and still be “isolated” or “purified.”

The polypeptides of the invention can be purified to homogeneity. It is understood, however, that preparations in which the polypeptide is not purified to homogeneity are useful and considered to contain an isolated form of the polypeptide. The critical feature is that the preparation allows for the desired function of the polypeptide, even in the presence of considerable amounts of other components. Thus, the invention encompasses various degrees of purity. In one embodiment, the language “substantially free of cellular material” includes preparations of the polypeptide having less than about 30% (by dry weight) other proteins (i.e., contaminating protein), less than about 20% other proteins, less than about 10% other proteins, or less than about 5% other proteins.

When a polypeptide is recombinantly produced, it can also be substantially free of culture medium, i.e., culture medium represents less than about 20%, less than about 10%, or less than about 5% of the volume of the protein preparation. The language “substantially free of chemical precursors or other chemicals” includes preparations of the polypeptide in which it is separated from chemical precursors or other chemicals that are involved in its synthesis. In one embodiment, the language “substantially free of chemical precursors or other chemicals” includes preparations of the polypeptide having less than about 30% (by dry weight) chemical precursors or other chemicals, less than about 20% chemical precursors or other chemicals, less than about 10% chemical precursors or other chemicals, or less than about 5% chemical precursors or other chemicals.

In one embodiment, a polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NOS: 2, 4, 8, 10 and 16 and the complements thereof. However, the invention also encompasses sequence variants. Variants include a substantially homologous protein encoded by the same genetic locus in an organism, i.e., an allelic variant. Variants also encompass proteins derived from other genetic loci in an organism, but having substantial homology to a polypeptide of the invention. Variants also include proteins substantially homologous to these polypeptides but derived from another organism, i.e., an ortholog. Variants also include proteins that are substantially homologous to these polypeptides that are produced by chemical synthesis. Variants also include proteins that are substantially homologous or identical to these polypeptides that are produced by recombinant methods.

As used herein, two proteins (or a region of the proteins) are substantially homologous or identical when the amino acid sequences are at least about 45-55%, typically at least about 70-75%, more typically at least about 80-85%, and most typically at least about 90-95% or more homologous or identical. A substantially homologous amino acid sequence, according to the present invention, will be encoded by a nucleic acid hybridizing to a nucleic acid sequence described herein, or portion thereof, under stringent conditions as more described above.

To determine the percent homology or identity of two amino acid sequences, or of two nucleic acids, the sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced in the sequence of one protein or nucleic acid for optimal alignment with the other protein or nucleic acid). The amino acid residues or nucleotides at corresponding amino acid positions or nucleotide positions are then compared. When a position in one sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the other sequence, then the molecules are homologous at that position. As used herein, amino acid or nucleic acid “homology” is equivalent to amino acid or nucleic acid “identity”. The percent homology between the two sequences is a function of the number of identical positions shared by the sequences (i.e., percent homology equals the number of identical positions/total number of positions times 100).

The invention also encompasses polypeptides having a lower degree of identity but having sufficient similarity so as to perform one or more of the same functions performed by a polypeptide encoded by a nucleic acid of the invention. Similarity is determined by conserved amino acid substitution. Such substitutions are those that substitute a given amino acid in a polypeptide by another amino acid of like characteristics. Conservative substitutions are likely to be phenotypically silent. Typically seen as conservative substitutions are the replacements, one for another, among the aliphatic amino acids Ala, Val, Leu, and Ine; interchange of the hydroxyl residues Ser and Thr, exchange of the acidic residues Asp and Glu, substitution between the amide residues Asn and GIn, exchange of the basic residues Lys and Arg and replacements among the aromatic residues Phe, Tyr. Guidance concerning which amino acid changes are likely to be phenotypically silent are found in Bowie et al., Science 247:1306-1310 (1990).

Preferred computer program methods to determine identify and similarity between two sequences include, but are not limited to, GCG program package (Devereux, J., et al., Nucleic Acids Res., 12(1):387 (1984)), BLASTP, BLASTN, FASTA (Atschul, S. F. et al., J. Molec. Biol., 215:403 (1990)).

A variant polypeptide can differ in amino acid sequence by one or more substitutions, deletions, insertions, inversions, fusions, and truncations or a combination of any of these. Further, variant polypeptides can be fully functional or can lack function in one or more activities. Fully functional variants typically contain only conservative variation or variation in non-critical residues or in non-critical regions. Functional variants can also contain substitution of similar amino acids that result in no change or an insignificant change in function. Alternatively, such substitutions may positively or negatively affect function to some degree.

Non-functional variants typically contain one or more non-conservative amino acid substitutions, deletions, insertions, inversions, or truncation or a substitution, insertion, inversion, or deletion in a critical residue or critical region. As indicated, variants can be naturally-occurring or can be made by recombinant means or chemical synthesis to provide useful and novel characteristics for the polypeptide. This includes preventing immunogenicity from pharmaceutical formulations by preventing protein aggregation.

Amino acids that are essential for function can be identified by methods known in the art, such as site-directed mutagenesis or alanine-scanning mutagenesis (Cunningham et al., Science, 244:1081-1085 (1989)). The latter procedure introduces single alanine mutations at every residue in the molecule. The resulting mutant molecules are then tested for biological activity in vitro, or in vitro proliferative activity. Sites that are critical for polypeptide activity can also be determined by structural analysis such as crystallization, nuclear magnetic resonance or photoaffinity labeling (Smith et al., J. Mol. Biol., 224:899-904 (1992); de Vos et al. Science, 255:306-312 (1992)).

The invention also includes polypeptide fragments or portions of the polypeptides of the invention, as well as fragments of the variants of the polypeptides described herein. As used herein, a fragment comprises at least 6 contiguous amino acids. Useful fragments include those that retain one or more of the biological activities of the polypeptide as well as fragments that can be used as an immunogen to generate polypeptide specific antibodies.

Biologically active fragments (peptides which are, for example, 6, 9, 12, 15, 20, 30, 35, 36, 37, 38, 39, 40, 50, 100 or more amino acids in length) can comprise a domain, segment, or motif that has been identified by analysis of the polypeptide sequence using well-known methods, e.g., signal peptides, extracellular domains, one or more transmembrane segments or loops, ligand binding regions, zinc finger domains, DNA binding domains, acylation sites, glycosylation sites, or phosphorylation sites.

The invention also provides fragments with immunogenic properties. These contain an epitope-bearing portion of the polypeptides and variants of the invention. These epitope-bearing peptides are useful to raise antibodies that bind specifically to a polypeptide or region or fragment. These peptides can contain at least 6, 7, 8, 9, 12, at least 14, or between at least about 15 to about 30 amino acids. The epitope-bearing peptide and polypeptides may be produced by any conventional means (Houghten, R. A., Proc. Natl. Acad. Sci. USA, 82:5131-5135 (1985)). Simultaneous multiple peptide synthesis is described in U.S. Pat. No. 4,631,211.

Fragments can be discrete (not fused to other amino acids or polypeptides) or can be within a larger polypeptide. Further, several fragments can be comprised within a single larger polypeptide. In one embodiment a fragment designed for expression in a host can have heterologous pre- and pro-polypeptide regions fused to the amino terminus of the polypeptide fragment and an additional region fused to the carboxyl terminus of the fragment.

The invention thus provides chimeric or fusion proteins. These comprise a polypeptide of the invention operatively linked to a heterologous protein having an amino acid sequence not substantially homologous to the polypeptide. “Operatively linked” indicates that the polypeptide protein and the heterologous protein are fused in-frame. The heterologous protein can be fused to the N-terminus or C-terminus of the polypeptide. In one embodiment the fusion protein does not affect function of the polypeptide per se. For example, the fusion protein can be a GST-fusion protein in which the polypeptide sequences are fused to the C-terminus of the GST sequences. The isolated polypeptide can be purified from cells that naturally express it, such as from mammary epithelium, purified from cells that have been altered to express it (recombinant), or synthesized using known protein synthesis methods.

In one embodiment, the protein is produced by recombinant DNA techniques. For example, a nucleic acid molecule encoding the polypeptide is cloned into an expression vector, the expression vector introduced into a host cell and the protein expressed in the host cell. The protein can then be isolated from the cells by an appropriate purification scheme using standard protein purification techniques.

Polypeptides often contain amino acids other than the 20 amino acids commonly referred to as the 20 naturally-occurring amino acids. Further, many amino acids, including the terminal amino acids, may be modified by natural processes, such as processing and other post-translational modifications, or by chemical modification techniques well known in the art. Common modifications that occur naturally in polypeptides are described in basic texts, detailed monographs, and the research literature, and they are well known to those of skill in the art.

Accordingly, the polypeptides also encompass derivatives or analogs in which a substituted amino acid residue is not one encoded by the genetic code, in which a substituent group is included, in which the mature polypeptide is fused with another compound, such as a compound to increase the half-life of the polypeptide (for example, polyethylene glycol), or in which the additional amino acids are fused to the mature polypeptide, such as a leader or secretory sequence or a sequence for purification of the mature polypeptide or a pro-protein sequence.

In general, polypeptides or proteins of the present invention can be used as a molecular weight marker on SDS-PAGE gels or on molecular sieve gel filtration columns using art-recognized methods. The polypeptides of the present invention can be used to raise antibodies or to elicit an immune response. The polypeptides can also be used as a reagent, e.g., a labeled reagent, in assays to quantitatively determine levels of the protein or a molecule to which it binds (e.g., a receptor or a ligand) in biological fluids. The polypeptides can also be used as markers for tissues in which the corresponding protein is preferentially expressed, either constitutively, during tissue differentiation, or in a diseased state. The polypeptides can be used to isolate a corresponding binding partner, e.g., receptor or ligand, such as, for example, in an interaction trap assay, and to screen for peptide or small molecule antagonists or agonists of the binding interaction.

In another aspect, the invention provides antibodies to the polypeptides and polypeptide fragments of the invention. The term “antibody” as used herein refers to immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, i.e., molecules that contain an antigen binding site that specifically binds an antigen. A molecule that specifically binds to a polypeptide of the invention is a molecule that binds to that polypeptide or a fragment thereof, but does not substantially bind other molecules in a sample, e.g., a biological sample, which naturally contains the polypeptide. Examples of immunologically active portions of immunoglobulin molecules include F(ab) and F(ab′)₂ fragments which can be generated by treating the antibody with an enzyme such as pepsin. The invention provides polyclonal and monoclonal antibodies that bind to a polypeptide of the invention; such antibodies can be made using methods known in the art. The term “monoclonal antibody” or “monoclonal antibody composition”, as used herein, refers to a population of antibody molecules that contain only one species of an antigen binding site capable of immunoreacting with a particular epitope of a polypeptide of the invention. A monoclonal antibody composition thus typically displays a single binding affinity for a particular polypeptide of the invention with which it immunoreacts.

Additionally, recombinant antibodies, such as chimeric and humanized monoclonal antibodies, comprising both human and non-human portions, which can be made using standard recombinant DNA techniques, are within the scope of the invention. Such chimeric and humanized monoclonal antibodies can be produced by recombinant DNA techniques known in the art, for example using methods described in PCT Publication No. WO 87/02671; European Patent Application 184,187; European Patent Application 171,496; European Patent Application 173,494; PCT Publication No. WO 86/01533; U.S. Pat. No. 4,816,567; European Patent Application 125,023; Better et al. (1988) Science, 240:1041-1043; Liu et al. (1987) Proc. Natl. Acad. Sci. USA, 84:3439-3443; Liu et al. (1987) J. Immunol., 139:3521-3526; Sun et al. (1987) Proc. Natl. Acad. Sci. USA, 84:214-218; Nishimura et al. (1987) Canc. Res., 47:999-1005; Wood et al. (1985) Nature, 314:446-449; and Shaw et al. (1988) J. Natl. Cancer Inst., 80:1553-1559); Morrison (1985) Science, 229:1202-1207; Oi et al. (1986) Bio/Techniques, 4:214; U.S. Pat. No. 5,225,539; Jones et al. (1986) Nature, 321:552-525; Verhoeyan et al. (1988) Science, 239:1534; and Beidler et al. (1988) J. Immunol., 141:4053-4060.

In general, antibodies of the invention (e.g. a monoclonal antibody) can be used to isolate a polypeptide of the invention by standard techniques, such as affinity chromatography or immunoprecipitation. A polypeptide specific antibody can facilitate the purification of natural polypeptide from cells and of recombinantly produced polypeptide expressed in host cells. Moreover, an antibody specific for a polypeptide of the invention can be used to detect the polypeptide (e.g., in a cellular lysate, cell supernatant, or tissue sample) in order to evaluate the abundance and pattern of expression of the polypeptide. Antibodies can be used diagnostically to monitor protein levels in tissue as part of a clinical testing procedure, e.g., to, for example, determine the efficacy of a given treatment regimen. Detection can be facilitated by coupling the antibody to a detectable substance. Examples of detectable substances include various enzymes, prosthetic groups, fluorescent materials, luminescent materials, bioluminescent materials, and radioactive materials. Examples of suitable enzymes include horseradish peroxidase, alkaline phosphatase, (β-galactosidase, or acetylcholinesterase; examples of suitable prosthetic group complexes include streptavidin/biotin and avidin/biotin; examples of suitable fluorescent materials include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride or phycoerythrin; an example of a luminescent material includes luminol; examples of bioluminescent materials include luciferase, luciferin, and aequorin, and examples of suitable radioactive material include ¹²⁵I, ¹³¹I, ³⁵S or ³H.

The present invention also pertains to diagnostic assays and prognostic assays used for prognostic (predictive) purposes to thereby treat an individual prophylactically. Accordingly, one aspect of the present invention relates to diagnostic assays for determining protein and/or nucleic acid expression as well as activity of proteins of the invention, in the context of a biological sample (e.g., blood, serum, cells, tissue) to thereby determine whether an individual is afflicted with a disease or disorder, or is at risk of developing a disorder, e.g., a neurodegenerative disorders such as ARSACS, associated with aberrant expression or activity. The invention also provides for prognostic (or predictive) assays for determining whether an individual is at risk of developing a disorder associated with activity or expression of proteins or nucleic acids of the invention.

Disorders which may be treated or diagnosed by methods described herein include, but are not limited to, neurodegenerative disease comprising one or more symptoms or effects selected from the group consisting of: reduced sensory nerve conduction, reduced motor nerve velocity, hypermyelination of retinal nerve fibers, atrophy of upper cerebellar vermis, absence of Purkinje cells and abnormal neuronal lipid storage. The invention is particularly suited to treat and diagnose ARSACS.

Another aspect of the invention pertains to monitoring the influence of agents (e.g., drugs, compounds) on the expression or activity of proteins of the invention in clinical trials.

An exemplary method for detecting the presence or absence of proteins or nucleic acids of the invention in a biological sample involves obtaining a biological sample from a test subject and contacting the biological sample with a compound or an agent capable of detecting the protein, or nucleic acid (e.g., mRNA, genomic DNA) that encodes the protein, such that the presence of the protein or nucleic acid is detected in the biological sample. A preferred agent for detecting mRNA or genomic DNA is a labeled nucleic acid probe capable of hybridizing to mRNA or genomic DNA sequences described herein. The nucleic acid probe can be, for example, a full-length nucleic acid, or a portion thereof, such as an oligonucleotide of at least 15, 30, 50, 100, 250 or 500 nucleotides in length and sufficient to specifically hybridize under stringent conditions to appropriate mRNA or genomic DNA. Other suitable probes for use in the diagnostic assays of the invention are described herein.

In one embodiment, the agent for detecting proteins of the invention is an antibody capable of binding to the protein, preferably an antibody with a detectable label. Antibodies can be polyclonal, or more preferably, monoclonal. An intact antibody, or a fragment thereof (e.g., Fab or F(ab′)₂) can be used. The term “labeled”, with regard to the probe or antibody, is intended to encompass direct labeling of the probe or antibody by coupling (i.e., physically linking) a detectable substance to the probe or antibody, as well as indirect labeling of the probe or antibody by reactivity with another reagent that is directly labeled. Examples of indirect labeling include detection of a primary antibody using a fluorescently labeled secondary antibody and end-labeling of a DNA probe with biotin such that it can be detected with fluorescently labeled streptavidin. In a preferred embodiment, the antibody is able to distinguish between complete or nearly complete proteins and truncated versions of the same protein.

The term “biological sample” is intended to include tissues, calls and biological fluids isolated from a subject, as well as tissues, cells and fluids present within a subject. For example, the sample can be obtained from a tissue selected from the group consisting of: brain tissue, CNS, lung, fetal lung, testis, lymphocytes, adipose, fibroblasts, skeletal muscle, pancreas, uterus, kidney, tonsil, embryo and isolated cells thereof. That is, the detection method of the invention can be used to detect mRNA, protein, or genomic DNA of the invention in a biological sample in vitro as well as in vivo. For example, in vitro techniques for detection of mRNA include Northern hybridizations and in situ hybridizations. In vitro techniques for detection of protein include enzyme linked immunosorbent assays (ELISAs), Western blots, immunoprecipitations and immunofluorescence. In vitro techniques for detection of genomic DNA include Southern hybridizations. Furthermore, in vivo techniques for detection of protein include introducing into a subject a labeled anti-protein antibody. For example, the antibody can be labeled with a radioactive marker whose presence and location in a subject can be detected by standard imaging techniques.

In one embodiment, the biological sample contains protein molecules from the test subject. Alternatively, the biological sample can contain mRNA molecules from the test subject or genomic DNA molecules from the test subject. A preferred biological sample is a serum sample or mammary epithelium isolated by conventional means from a subject. A nucleic acid sample is a sample, e.g., a biological sample, which contains nucleic acid molecules.

The invention also encompasses kits for detecting the presence of proteins or nucleic acid molecules of the invention in a biological sample. For example, the kit can comprise a labeled compound or agent capable of detecting protein or mRNA in a biological sample; means for determining the amount of in the sample; and means for comparing the amount of in the sample with a standard. The compound or agent can be packaged in a suitable container. The kit can further comprise instructions for using the kit to detect protein or nucleic acid.

The diagnostic methods described herein can also be utilized to identify subjects having or at risk of developing a disease or disorder associated with aberrant expression or activity of proteins and nucleic acid molecules of the invention. For example, the assays described herein can be utilized to identify a subject having or at risk of developing a disorder associated with Spastin protein or spastin nucleic acid expression or activity such as a neurodegenerative disorder. Thus, the present invention provides a method for identifying a disease or disorder associated with aberrant expression or activity of proteins or nucleic acid molecules of the invention, in which a test sample is obtained from a subject and protein or nucleic acid molecule (e.g., mRNA, genomic DNA) is detected, wherein the presence of an altered protein or nucleic acid molecule is diagnostic for a subject having or at risk of developing a disease or disorder associated with aberrant expression or activity of the protein or nucleic acid sequence of the invention. In certain embodiments as described herein, it is valuable to determine the genotype of an individual, particularly where a specific allelic form is associated with disease. For example, it will be valuable for purposes of diagnosis to determine an individual's genotype for the C52454T mutation with respect to ARSACS diagnosis, i.e., to identify alteration in the spastin gene or Spastin protein.

Detection of the alteration can involve the use of a probe/primer in a polymerase chain reaction (PCR) (see, e.g., U.S. Pat. Nos. 4,683,195 and 4,683,202), such an anchor PCR or RACE PCR, or, alternatively, in a ligation chain reaction (LCR) (see, e.g., Landegran et al. (1988) Science, 241:1077-1080; and Nakazawa et al. (1994) PNAS, 91:360-364), the latter of which can be particularly useful for detecting point mutations (see Abravaya et al. (1995) Nucleic Acids Res., 23:675-682). This method can include the steps of collecting a sample of cells from a patient, isolating nucleic acid molecules (e.g., genomic, mRNA or both) from the cells of the sample, contacting the nucleic acid sample with one or more primers which specifically hybridize to the gene under conditions such that hybridization and amplification of the gene (if present) occurs, and detecting the presence or absence of an amplification product, or detecting the size of the amplification product and comparing the length to a control sample. It is anticipated that PCR and/or LCR may be desirable to use as a preliminary amplification step in conjunction with any of the techniques used for detecting mutations described herein. In one embodiment allele-specific primers are utilized.

Alternative amplification methods include: self sustained sequence replication (Guatelli, J. C. et al. (1990) Proc. Natl. Acad. Sci. USA, 87:1874-1878), transcriptional amplification system (Kwoh, D. Y. et al., (1989) Proc. Natl. Acad. Sci. USA, 86:1173-1177), Q-Beta Replicase (Lizardi, P. M. et al., (1988) Bio/Technology, 6:1197), or any other nucleic acid amplification method, followed by the detection of the amplified molecules using techniques well known to those of skill in the art. These detection schemes are especially useful for the detection of nucleic acid molecules if such molecules are present in very low numbers.

In an alternative embodiment, mutations in a given gene from a sample cell can be identified by alterations in restriction enzyme cleavage patterns. For example, sample and control DNA is isolated, amplified (optionally), digested with one or more restriction endonucleases, and fragment length sizes are determined by gel electrophoresis and compared. Differences in fragment length sizes between sample and control DNA indicate mutations in the sample DNA. Moreover, the use of sequence specific ribozymes (see, for sample, U.S. Pat. No. 5,498,531) can be used to score for the presence of specific mutations, e.g., the C5254T mutation, by development or loss of a ribozyme cleavage site.

In other embodiments, genetic mutations can be identified by hybridizing a sample and control nucleic acids, e.g., DNA or RNA, to high density arrays containing many oligonucleotide probes (Cronin, M. T. et al. (1996) Human Mutation, 7:244-255; Kozal, M. J. et al. (1996) Nature Medicine, 2:753-759). For example, genetic mutations can be identified in two dimensional arrays containing light-generated DNA probes as described in Cronin, M. T. et al. supra. Briefly, a first hybridization array of probes can be used to scan through long stretches of DNA in a sample and control to identify base changes between the sequences by making linear arrays of sequential overlapping probes. This step allows the identification of point mutations. This step is followed by a second hybridization array that allows the characterization of specific mutations by using smaller, specialized probe arrays complementary to all variants or mutations detected. Each mutation array is composed of parallel probe sets, one complementary to the wild-type gene and the other complementary to the mutant gene.

In yet another embodiment, any of a variety of sequencing reactions known in the art can be used to directly sequence the gene and detect specific mutations by comparing the sequence of the gene from the sample with the corresponding wild-type (control) gene sequence. Examples of sequencing reactions include those based on techniques developed by Maxim and Gilbert ((1997) PNAS, 74:560) or Sanger ((1977) PNAS, 74:5463). It is also contemplated that any of a variety of automated sequencing procedures can be utilized when performing the diagnostic assays ((1995) Biotechniques, 19:448), including sequencing by mass spectrometry (see, e.g., PCT International Publication No. WO 94/16101; Cohen et al. (1996) Adv. Chromatogr., 36:127-162; and Griffin et al. (1993) Appl. Biochem. Biotechnol., 38:147-159).

Other methods for detecting mutations include methods in which protection from cleavage agents is used to detect mismatched bases in RNA/RNA or RNA/DNA heteroduplexes (Myers et al. (1985) Science, 230:1242). In general, the art technique of “mismatch cleavage” starts by providing heteroduplexes formed by hybridizing (labeled) RNA or DNA containing the wild-type sequence with potentially mutant RNA or DNA obtained from a tissue sample. The double-standard duplexes are treated with an agent that cleaves single-stranded regions of the duplex such as which will exist due to base pair mismatches between the control and sample strands. For instance, RNA/DNA duplexes can be treated with Rnase and DNA/DNA hybrids treated with S1 nuclease to enzymatically digest the mismatched regions. After digestion of the mismatched regions, the resulting material is then separated by size on denaturing polyacrylamide gels to determine the site of mutation. See, for example Cotton et al. (1988) Proc. Natl. Acad. Sci. USA, 85:4397; Saleeba et al. (1992) Methods Enzymol., 217:286-295. In certain embodiments, the control DNA or RNA can be labeled for detection.

In still another embodiment, the mismatch cleavage reaction employs one or more proteins that recognize mismatched base pairs in double-stranded DNA (so called “DNA mismatch repair” enzymes) in defined systems for detecting and mapping point mutations in cDNAs obtained from samples of cells. For example, the mutY enzyme of E. coli cleaves A at G/A mismatches and the thymidine DNA glycosylase from HeLa cells cleaves T at G/T mismatches (Hsu et al. (1994) Carcinogenesis, 15:1657-1662). According to an exemplary embodiment, a probe based on an nucleotide sequence of the invention is hybridized to a cDNA or other DNA product from a test cell(s). The duplex is treated with a DNA mismatch repair enzyme, and the cleavage products, if any, can be detected from electrophoresis protocols or the like. See, for example, U.S. Pat. No. 5,459,039.

In other embodiments, alterations in electrophoretic mobility will be used to identify mutations in nucleic acid molecules described herein. For example, single strand conformation polymorphism (SSCP) may be used to detect differences in electrophoretic mobility between mutant and wild type nucleic acids (Orita et al. (1989) Proc. Natl. Acad. Sci. USA, 86:2766, see also Cotton (1993) Mutat Res, 285:125-144; and Hayashi (1992) Genet Anal. Tech. Appl., 9:73-79). Single-stranded DNA fragments of sample and control nucleic acids will be denatured and allowed to renature. The secondary structure of single-stranded nucleic acids varies according to sequence, and the resulting alteration in electrophoretic mobility enables the detection of even a single base change. The DNA fragments may be labeled or detected with labeled probes. The sensitivity of the assay may be enhanced by using RNA (rather than DNA), in which the secondary structure is more sensitive to a change in sequence. In one embodiment, the subject method utilizes heteroduplex analysis to separate double stranded heteroduplex molecules on the basis of changes in electrophoretic mobility (Keen et al. (1991) Trends Genet., 7:5).

In yet another embodiment the movement of mutant or wild-type fragments in polyacrylamide gels containing a gradient of denaturant is assayed using denaturing gradient gel electrophoresis (DGGE) (Myers et al. (1985) Nature, 313:495). When DGGE is used as the method of analysis, DNA will be modified to insure that it does not completely denature, for example by adding a GC clamp of approximately 40 bp of high-melting GC-rich DNA by PCR. In a further embodiment, a temperature gradient is used in place of a denaturing gradient to identify differences in the mobility of control and sample DNA (Rosenbaum and Reissner (1987) Biophys. Chem., 265:12753).

Examples of other techniques for detecting point mutations include, but are not limited to, selective oligonucleotide hybridization, selective amplification, or selective primer extension. For example, oligonucleotide primers may be prepared in which the known mutation is placed centrally and then hybridized to target DNA under conditions which permit hybridization only if a perfect match is found (Saiki et al. (1986) Nature, 324:163); Saiki et al. (1989) Proc. Natl. Acad. Sci. USA, 86:6320). Such allele-specific oligonucleotides are hybridized to PCR amplified target DNA.

Alternatively, allele specific amplification technology that depends on selective PCR amplification may be used in conjunction with the instant invention. Oligonucleotides used as primers for specific amplification may carry the mutation of interest in the center of the molecule (so that amplification depends on differential hybridization) (Gibbs et al. (1989) Nucleic Acids Res., 17:2437-2448) or at the extreme 3′ end of one primer where, under appropriate conditions, mismatch can prevent, or reduce polymerase extension (Prossner (1993) Tibtech, 11:238). In addition it may be desirable to introduce a novel restriction site in the region of the mutation to create cleavage-based detection (Gasparini et al. (1992) Mol. Cell Probes, 6:1). It is anticipated that in certain embodiments amplification may also be performed using Taq ligase for amplification (Barany (1991) Proc. Natl. Acad. Sci. USA, 88:189). In such cases, ligation will occur only if there is a perfect match at the 3′ end of the 5′ sequence making it possible to detect the presence of a known mutation at a specific site by looking for the presence or absence of amplification. Single base extension (SBE) and SBE fluorescence resonance energy transfer (SBE-FRET) can also be used to identify the specific nucleotide which occupies a given position in a nucleic acid molecule.

The methods described herein may be performed, for example, by utilizing pre-packaged diagnostic kits comprising at least one probe nucleic acid molecule or antibody reagent described herein, which may be conveniently used, e.g., in clinical settings to diagnose patients exhibiting symptoms or family history of a disease or illness involving a gene of the present invention. Any cell type or tissue in which the gene is expressed may be utilized in the prognostic assays described herein.

The invention will now be described by the following non-limiting examples. The teachings of all references cited herein are incorporated herein by reference in their entirety.

EXEMPLIFICATION

Methods

All subjects participating in this study gave informed consent according to institutional and national standards (29). Sequence analysis was performed on 24 ARSACS patients from 17 families.

BAC/PAC DNA Preparation

Small quantities of DNA were prepared from BAC and PAC cell cultures (12.5 μl Chloramphenicol for BACS, 30 μg/ml Kanamycin for PACs) using a modified alkaline lysis procedure according to a published protocol (30). Larger quantities of DNA for the construction of libraries and direct sequencing were prepared using Qiagen (Qiagen, Valencia, Calif.) or Nucleobond columns (The Nest Group, Southboro, Mass.) according to the manufacturers' protocols.

M13 Library Construction and Preparation of M13 Single-Stranded DNA

BAC and PAC DNA was sheared in a sonicator to an average size of 2 kb and the ends were made blunt with Mung Bean Nuclease (New England Biolabs, Beverly, Mass.). The fragments were gel-purified, and subcloned into an M13 mp18 Sma I-cut dephosphorylated cloning vector (Amersham, Uppsala, Sweden). Ligation reactions were transformed into XL2-Blue competent cells (Stratagene, LaJolla, Calif.). Phage plaques of M13 subclones from the BACs and PACs were grown overnight in 0.5 ml of 2× YT media with 10 μl of log phase TG-1 cells. Single-stranded M13 DNA for sequencing was purified from 100 μl of the culture supernatant with magnetic beads (PerSeptive Diagnostics, Cambridge, Mass.) according to the manufacturers instructions.

Sequencing

Fluorescent sequencing of PCR products and M13 single-stranded DNA was accomplished using the Dye Primer Cycle Sequencing Ready Reaction kit (Perkin Elmer, Foster City, Calif.). Sequencing reactions contained approximately 400 ng of template in 1.5 μl and 3 μl of assay mixture for each primer. The thermal cycling parameters for the sequencing reactions were: 96° C. for 10 seconds, 55° C. for 5 seconds, and 70° C. for 1 minute (15 cycles) followed by 96° C. for 10 seconds, and 70° C. for 1 minute (15 cycles). Reaction products for each primer were combined and purified with an ethanol precipitation. Sequence samples were prepared, loaded, and run on ABI 377 sequencers according to the manufacturer's instructions (Perkin Elmer). The sequences were assembled into contigs and analyzed with the STADEN software package (version 1997.1) (31, 32) and Auto Assembler (version 2.0) (Perkin Elmer). Direct sequencing of BACs was accomplished with Dye Terminator chemistry according to a previously published protocol (33). The sequence of the entire mouse and human ORFs was verified by either sequencing unambiguously on both strands or by sequencing a single strand with both the Dye Primer and the Dye Terminator reaction systems. All sequences were compared with GenBank databases and dbEST using the Search Launcher Batch Client software for Macintosh from Baylor College of Medicine (34) with Repeat/Masker prescreening.

Computational Analyses

World Wide Web-based hyper-text (http) sequence analysis included (using default parameters): BLAST; FASTA; PSORT; EXPASY Proteomics tools; BCM Search Launcher; COILS (35) web server, and the ftp site, mac-search-launcher.

Mutation Analysis

50 ng of genomic DNA, extracted from peripheral blood leukocytes, was amplified using the primers in FIG. 7. Primer pairs were designed using the web-based version of the Primer 3.0 program and PCR reactions were individually optimized. The resulting products were purified using magnetic beads (PerSeptive Diagnostics) according to the manufacturer's instructions and sequenced as above.

RNA Preparation and Northern Blot Analysis

Total RNA was extracted using the guanidinium/CsCl method from skin fibroblast cell lines from ARSACS patients and a control individual; the cell lines were grown in Eagle modified MEM (CellGro, Herndon, Va.) with 10% FBS (Canadian Life Technology, Burlington, Ontario). 10 μg of RNA was electrophoresed in a 1% agarose gel and then transferred to a nylon membrane (Magna Charge, MSI, Westboro, Mass.) by capillary transfer with 20× SSC buffer. Pre-transfer alkaline hydrolysis of the gel was performed with 0.05M NaOH. The ³²P-labeled spastin probe was generated by random priming with the Rediprime II system (Amersham) using the 1.8 kb insert from an IMAGE cDNA clone (279258) purified after separation on low melting point agarose (Life Technologies, Rockville, Md.). Hybridization for both the fibroblast blot and the multiple tissue northern blot (MTN, Human I #7760-1, Clontech) was done in ExpressHyb buffer (Clontech, Palo Alto, Calif.) followed by washing according to manufacturer's instructions. The size standard for both northern blots was a 0.249.5 kb RNA ladder (Life Technologies).

RT-PCR

500 ng of total RNA from skin fibroblasts of ARSACS patients and controls, as well as a commercial preparation of total RNA from cerebellum (Clontech), were amplified using sense and antisense primers (FIG. 7) and the Superscript one step kit (Life Technologies). In all cases a parallel control reaction was set up in the absence of RT. The resulting products were purified and sequenced as above.

In Situ Hybridizations

Oligonucleotides complementary to nucleotides 11,009-11,055 of the human spastin gene (probe NIB226-1) and a sense 45-mer for the same region were synthesized and purified (MedProbe, Oslo, Norway). To exclude the possibility of any cross-hybridization to other human mRNAs, homology searches were carried out. A database search revealed no significant homologies, except for the intended targets. The oligonucleotides were subsequently labeled with a ³⁵S-labeled dATP (NEG 034H, NEN DuPont, Boston, Mass.) at the 3′ end using terminal dideoxy nucleotides transferase to a specific activity of 2×10⁹ cpm/μg and purified on a Nensorb 20 column.

The tissue was cut to 14 μm thickness in a cryostat, thawed onto Fisher probe on (+) slides (Fisher Biotech, Springfield, N.J.), and processed for in situ hybridization according to Schalling et al (36). In brief, sections were incubated at 42° C. for 15-18 hours with 106 cpm of labeled probe per 100 μl of a solution containing 50% formamide, 4× SSC, 1× Denhardt's solution, 1% sarcosyl, 0.02 M sodium phosphate (NaPO₄, pH 7.0) and 10% dextran sulfate mixed with 500 μg/ml sonicated salmon sperm DNA and 200 mM dithiothreitol. Sections were rinsed in 1× SSC at 55° C. for one hour, dried and exposed to x-ray film (Amersham Hyperfilm β-max) for 14-21 days.

Mouse BAC Clone and Radiation Hybrid (RH) Panel Analysis

The clone containing the mouse genomic sequence (418_B_(—)11) is from a 129 SV mouse BAC library, CitbCJ7B cloned in the vector pBeloBAC11 (Research Genetics, Huntsville, Ala.). The RH mapping of mouse spastin was performed using the T31 mouse-hamster hybrid mapping panel (11). The initial attempts with several mouse spastin primers failed due to the amplification of a hamster PCR product of similar size to the mouse product. A hamster PCR product was sequenced, which revealed minor sequence differences with mouse spastin. The successful mouse spastin primers were MARS-3F ((TCATTCATATGTCCCAGGGACATGT; SEQ ID NO: 72) and MARS-3R (CTACTAGAACTGCATGTGCCGC; SEQ ID NO: 73). The RH vector obtained from testing the T31 panel was compared to the reference map generated at MIT (12) using the “placement” function of RHMAPPER

Computation of the P_(excess) Statistic

Seven-marker haplotypes for 55 ARSACS and 58 normal chromosomes were obtained from 68 obligate carrier parents by not counting copies that were considered to be identical by descent within a pedigree (5). Marker haplotypes were constructed using the SIMWALK2 program (37). The simple linkage disequilibrium mapping measure P_(excess)=(p_(affected)−p_(normal))(1−p_(normal)) was calculated from the frequencies of haplotypes.

While this invention has been particularly shown and described with references to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims.

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SEQUENCE LISTING <160> NUMBER OF SEQ ID NOS: 73 <210> SEQ ID NO 1 <211> LENGTH: 12793 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 1 atgatttaca ggaagaccat gtactcagct gcagcttcta aatccagaac gatttgcacg 60 tcttatcaag gaagtaatga atacattctg gcctggcaga gaattgattg ttcaatggta 120 tccatttgat gaaaacagaa atcacccatc tgtttcatgg cttaagatgg tttggaaaaa 180 tctttatata catttttcag aggatttgac tttatttgat gagatgccac ttatccccag 240 aactatacta gaggaaggtc agacatgtgt ggaactcatt agactcagga ttccatcgtt 300 agtcatttta gacgatgaat ctgaagcaca gcttccagaa tttttagcag acattgtaca 360 aaaacttgga gggtttgtcc ttaaaaaatt agatgcatct atacaacatc cgcttattaa 420 aaaatatatt cattcaccat taccaagtgc tgttttgcag ataatggaga agatgccatt 480 gcagaaattg tgtaatcaaa taacttcgct acttccaaca cacaaagatg ccctgaggaa 540 gttcttggct agtttaaccg atagcagtga gaaagagaaa agaattattc aagaattggc 600 aatattcaag cgcattaacc attcttctga tcagggaatt tcctcttata caaaattgaa 660 aggttgtaaa gtcttacacc atactgccaa actcccagca gatctgcgac tttctatttc 720 agtaatagac agtagtgatg aagctactat tcgtctggca aacatgttga aaatagaaca 780 gttaaagacc actagctgct taaagcttgt tttaaaagat attgaaaatg cattttattc 840 acatgaagag gtaacacagc ttatgttatg ggtccttgag aatctatctt ctcttaaaaa 900 tgagaatcca aatgtgcttg agtggttaac accattaaaa ttcatccaga tatcacagga 960 acagatggta tcagctggtg aactctttga ccctgatata gaagtactaa aggatctctt 1020 ttgtaatgaa gaaggaacct atttcccacc ctcagttttt acctcaccag atattcttca 1080 ctccttaaga cagattggtt taaaaaacga agccagtctc aaagaaaagg atgttgtgca 1140 agtggcaaaa aaaattgaag ccttacaggt cggtgcttgt cctgatcaag atgttcttct 1200 gaagaaagcc aaaaccctct tactggtttt aaataagaat cacacactgt tgcaatcatc 1260 tgaaggaaag atgacattga agaaaataaa atgggttcca gcctgcaagg aaaggcctcc 1320 aaattatcca ggctctttgg tctggaaagg agatctctgt aatctctgtg caccaccaga 1380 tatgtgtgat gtaggccatg caattctcat tggctcctca cttcctcttg ttgaaagtat 1440 ccatgtaaac ctggaaaaag cattagggat cttcacaaaa cctagcctta gtgctgtctt 1500 aaaacacttt aaaattgttg ttgattggta ttcttcaaaa acctttagtg atgaagacta 1560 ctatcaattc cagcatattt tgcttgagat ttacggattc atgcatgatc atctaaatga 1620 agggaaagat tcttttagag ccttaaaatt tccatgggtt tggactggca aaaagttttg 1680 tccacttgcc caggctgtga ttaaaccaat ccatgatctt gaccttcagc cttatttgca 1740 taatgtacct aaaaccatgg caaaattcca ccaactattt aaggtctgtg gttcaataga 1800 ggagttgaca tcagatcata tttccatggt tattcagaag atatatctca aaagtgacca 1860 agatctcagt gaacaagaaa gcaaacaaaa tcttcatctt atgttgaata ttatcagatg 1920 gctgtatagc aatcagattc cagcaagccc caacacacca gttcctatac atcatagcaa 1980 aaatccttct aaacttatca tgaagccaat tcacgaatgc tgttattgtg acattaaagt 2040 tgatgacctt aatgacttac ttgaagattc tgtggaacca atcattttgg tgcatgagga 2100 catacccatg aaaactgcag aatggctaaa agttccatgc cttagtacaa gactgataaa 2160 tcctgaaaac atgggatttg agcagtcagg acaaagagag ccacttactg taagaattaa 2220 aaatattctg gaagaatacc cttcagtgtc agatattttt aaagaactac ttcaaaacgc 2280 tgatgatgca aatgcaacag aatgcagttt cttgattgat atgagaagaa atatggacat 2340 aagagagaat ctcctagacc cagggatggc agcttgtcat ggacctgctt tgtggtcatt 2400 caacaattct caattctcag attcagattt tgtgaacata actaggttag gagaatcttt 2460 aaaaagggga gaagttgaca aagttggaaa atttggtctt ggatttaatt ctgtgtacca 2520 tatcactgac attcccatca ttatgagtcg ggaattcatg ataatgttcg atccaaacat 2580 aaatcatatc agtaaacaca ttaaagacaa atccaatcct gggatcaaaa ttaattggag 2640 taaacaacag aaaagactta gaaaatttcc taatcagttc aaaccattta tagatgtatt 2700 tggctgtcag ttacctttga ctgtagaagc accttacagc tataatggaa cccttttccg 2760 actgtccttt agaactcaac aggaagcaaa agtgagtgaa gttagtagta cgtgctacaa 2820 tacagcagat atttattctc ttgtggatga atttagtctc tgtggacaca ggcttatcat 2880 tttcactcag agtgtaaagt caatgtattt gaagtacttg aaaattgagg aaaccaaccc 2940 cagtttagca caagatacag taataattaa aaaaaaatcc tgctcttcca aagcattgaa 3000 cacacctgtc ttaagtgttt taaaagaggc tgctaagctc atgaagactt gcagcagcag 3060 taataaaaag cttcccagtg atgaaccaaa gtcatcttgc attcttcaga tcacagtgga 3120 agaatttcac catgtgttca gaaggattgc tgatttacag tcgccacttt ttagaggtcc 3180 agatgatgac ccagctgctc tctttgaaat ggctaagtct ggccaatcaa aaaagccatc 3240 agatgagttg tcacagaaaa cagtagagtg taccacgtgg cttctgtgta cttgcatgga 3300 cacaggagag gctctgaagt tttccctgag tgagagtgga agaagactag gactggttcc 3360 atgtggggca gtaggagttc agctgtcaga aatccaggac cagaagtgga cagtgaaacc 3420 acacattgga gaggtgtttt gctatttacc tttacgaata aaaacaggct tgccagttca 3480 tatcaatggg tgctttgctg ttacatcaaa taggaaagaa atctggaaaa cagatacaaa 3540 aggacgatgg aataccacgt tcatgagaca tgttattgtg aaagcttact tacaggtact 3600 gagtgtctta cgggacctgg ccactagtgg ggagctaatg gattatactt actatgcagt 3660 atggcccgat cctgatttag ttcatgatga tttttctgta atttgccaag gattttatga 3720 agatatagct catggaaaag ggaaagaact gaccaaagtc ttctctgatg gatctacttg 3780 ggtttccatg aagaacgtaa gatttctaga tgactctata cttaaaagaa gagatgttgg 3840 ttcagcagcc ttcaagatat ttttgaaata cctcaagaag actgggtcca aaaacctttg 3900 tgctgttgaa cttccttctt cggtaaaatt aggatttgaa gaagctggct gcaaacagat 3960 actacttgaa aacacatttt cagagaaaca gtttttttct gaagtgtttt ttccaaatat 4020 tcaagaaatt gaagcagaac ttagagatcc tttaatgatc tttgttctaa atgaaaaagt 4080 tgatgagttc tcgggagttc ttcgtgttac tccatgtatt ccttgttcct tggaggggca 4140 tcctttggtt ttgccatcaa gattgatcca ccccgaagga cgagttgcaa agttatttga 4200 tattaaagat gggagattcc cttatggttc tactcaggat tatctcaatc ctattatttt 4260 gattaaacta gttcagttag gtatggcaaa agatgatatt ttatgggatg atatgctaga 4320 acgtgcagtg tcagtagctg aaattaataa aagtgatcat gttgctgcat gcctaagaag 4380 tagtatctta ttgagtctta tcgatgagaa actaaaaata agggatccta gagcaaagga 4440 ttttgctgca aaatatcaaa caatccgctt ccttccattt ctgacaaaac cagcaggttt 4500 ttctttggac tggaaaggca acagttttaa gcctgaaacc atgtttgcag caactgacct 4560 ttatacagct gaacatcaag atatagtttg tcttttgcaa ccaattctaa atgaaaattc 4620 ccattctttt agaggttgtg gttcagtgtc attggctgtt aaagagtttt tgggattact 4680 caagaagcca acagttgatc tggttataaa ccaattgaaa gaagtagcaa aatcagttga 4740 tgatggaatt acactgtacc aggagaatat caccaatgct tgctacaaat accttcatga 4800 agccttgatg caaaatgaaa tcactaagat gtcaattatt gataagttaa aaccctttag 4860 cttcattcta gttgagaatg catatgttga ctcagaaaag gtttcttttc atttaaattt 4920 tgaggcggca ccataccttt atcagttgcc taataagtat aaaaataatt tccgcgaact 4980 ttttgaaacc gtgggtgtga ggcagtcatg cactgttgaa gattttgctc ttgttttgga 5040 atctattgat caagaaagag gaacaaagca aataacagaa gagaattttc agctttgccg 5100 acgaataatc agtgaaggaa tatggagtct cattagagaa aagaaacaag aattttgtga 5160 gaaaaattat ggcaagatat tattgccaga tactaatctt atgcttctcc ctgctaaatc 5220 gttatgctac aatgattgcc cttggataaa agtaaaggat accactgtaa aatattgtca 5280 tgctgacata cccagggaag tagcagtaaa actaggagca gtcccaaagc gacacaaagc 5340 cttagaaaga tatgcatcca atgtctgttt tacaacactt ggcacagaat ttgggcagaa 5400 agaaaaattg accagcagaa ttaagagcat ccttaatgca tatccttctg aaaaggaaat 5460 gttgaaagag cttcttcaaa atgctgatga tgcaaaggcg acagaaatct gttttgtgtt 5520 tgatcctaga cagcatccag ttgatagaat atttgatgat aagtgggccc cattgcaagg 5580 gccagcactt tgtgtgtaca acaaccagcc atttacagaa gatgatgtta gaggaattca 5640 gaatcttgga aaaggcacga aagagggaaa tccttataaa actggacagt atggaatagg 5700 attcaattct gtgtatcata tcacagactg cccatctttt atttctggca atgacatcct 5760 gtgtattttt gatcctcatg ccagatatgc accaggggcc acatccatta gtcccggacg 5820 catgtttaga gatttggatg cagattttag gacacagttc tcagatgttc tggatcttta 5880 tctgggaacc cattttaaac tggataattg cacaatgttc agatttcctc ttcgtaatgc 5940 agaaatggca aaagtttcgg aaatttcgtc tgttccagca tcagacagaa tggtccagaa 6000 tcttttggac aaactgcgct cagatggggc agaacttcta atgtttctta atcacatgga 6060 aaaaatttct atttgtgaaa tagataagag tactggagct ctaaatgtgc tgtattcagt 6120 aaagggcaaa atcacagatg gagacagatt gaaaaggaaa caatttcatg catctgtaat 6180 tgatagtgtt actaaaaaga ggcagctcaa agacatacca gttcaacaaa taacctatac 6240 tatggatact gaggactctg aaggaaatct tactacgtgg ctaatttgta atagatcagg 6300 cttttcaagt atggagaaag tatctaaaag tgtcatatca gctcacaaga accaagatat 6360 tactcttttc ccacgtggtg gagtagctgc ctgcattact cacaactata aaaaacccca 6420 tagggccttc tgttttttgc ctctttcttt ggagactggg ctgccatttc atgtgaatgg 6480 ccactttgca ctggattcag ccagaaggaa cctgtggcgt gatgataatg gagttggtgt 6540 tcgaagtgac tggaataaca gtttaatgac agcattaata gctcctgcat atgttgaatt 6600 gctaatacag ttaaaaaaac ggtatttccc tggttctgat ccaacattat cagtgttaca 6660 gaacacccct attcatgttg taaaggacac tttaaagaag tttttatcgt ttttcccagt 6720 taaccgtctt gatctacagc cagatttata ttgtctagtg aaagcacttt acaattgcat 6780 tcacgaagac atgaaacgtc ttttacctgt tgtgcgggct ccaaatattg atggctctga 6840 cttgcactct gcagttataa ttacttggat caatatgtct acttctaata aaactagacc 6900 attttttgac aatttactac aggatgaatt acaacacctt aaaaatgcag attataatat 6960 caccacacgc aaaacagtag cagagaatgt ctataggctg aaacatctcc ttttagaaat 7020 tggtttcaac ttggtttata actgtgatga aactgctaat ctttaccact gtcttataga 7080 tgcagatatt cctgttagtt atgtgacccc tgctgatatc agatcttttt taatgacatt 7140 ttcctctcct gacactaatt gccatattgg gaagctgcct tgtcgtctgc agcagactaa 7200 tctaaaactt tttcatagtt taaaactttt agttgattat tgttttaaag atgcagaaga 7260 aaatgagatt gaagttgagg gattgcccct tctcatcaca ctggacagtg ttttgcaaac 7320 ttttgatgca aaacgaccca agtttctaac aacatatcat gaattgattc catcccgcaa 7380 agacttgttt atgaatacat tatatttgaa atatagtaat attttattga actgtaaagt 7440 tgcaaaagtg tttgacattt ccagctttgc tgatttgtta tcctctgtgt tgcctcgaga 7500 atataagacc aaaagttgca caaagtggaa agacaatttt gcaagtgagt cttggcttaa 7560 gaatgcatgg cattttatta gtgaatctgt aagtgtgaaa gaagatcagg aagaaacaaa 7620 accaacattt gacattgttg ttgatactct aaaagactgg gcattgcttc caggaacaaa 7680 gtttactgtt tcagccaacc agcttgtggt tcctgaagga gatgttctgc ttcctctcag 7740 ccttatgcac attgcagttt ttccaaatgc ccagagtgat aaagtttttc atgctctaat 7800 gaaagccggc tgtattcagc ttgctttgaa caaaatctgt tccaaagaca gtgcatttgt 7860 tcctttgttg tcatgtcaca cagcaaatat agagagcccc acaagcatct tgaaggctct 7920 acattatatg gtccaaactt caacatttag agcagaaaaa ttagtagaaa atgattttga 7980 ggcacttttg atgtatttca actgcaattt gaatcatttg atgtcccaag atgatataaa 8040 aattctaaag tcacttccgt gctataaatc catcagtggc cgctatgtaa gcattggaaa 8100 atttggaaca tgctacgtac ttacaaaaag tatcccttca gctgaagtgg agaaatggac 8160 acaatcatca tcatctgcat ttcttgaaga aaaaatacac ttaaaagaac tatatgaggt 8220 gattggttgt gtacctgtag atgatcttga ggtatatttg aaacacctct taccaaaaat 8280 tgaaaatctc tcttatgatg caaaattaga gcacttgatc taccttaaga atagattatc 8340 aagtgctgag gaattatcag agattaagga acaacttttt gaaaaactgg aaagtttatt 8400 gataatccat gatgctaaca gtagactaaa gcaagcaaag catttctatg atagaactgt 8460 gagagttttt gaagttatgc ttcctgaaaa attgtttatt cctaatgatt tctttaagaa 8520 attggaacaa cttataaaac ccaaaaatca tgttacattt atgacatcct gggtggaatt 8580 cttaagaaat attggactaa aatacatact ttctcagcag cagttgttac agtttgctaa 8640 ggaaatcagt gtgagggcta atacagaaaa ctggtccaaa gaaacattgc aaaatacagt 8700 tgatatcctt ctgcatcata tattccaaga acgaatggat ttgttatctg gaaattttct 8760 gaaagaacta tctttaatac cattcttatg tcctgagcgg gcccccgcgg aattcattag 8820 atttcatcct caatatcaag aggtaaatgg aacacttcct cttataaagt tcaatggagc 8880 acaggtaaat ccaaaattca agcaatgtga tgtactccag ctgttatgga catcctgccc 8940 tattcttcca gagaaagcta cacccttaag cattaaagaa caagaaggta gtgaccttgg 9000 tccacaagaa cagcttgaac aagttttaaa tatgcttaat gttaacctgg atcctcctct 9060 tgataaggta atcaataact gcagaaacat atgcaacata acgacgttgg atgaagaaat 9120 ggtaaaaact agagcaaaag tcttaaggag catatatgaa ttcctcagtg cagaaaaaag 9180 ggaatttcgt tttcagttgc gaggggttgc ttttgtgatg gtagaagatg gttggaaact 9240 tctgaagcct gaggaggtag tcataaacct agaatatgaa tctgatttta aaccttattt 9300 gtacaagcta cctttagaac ttggcacatt tcaccagttg ttcaaacact taggtactga 9360 agatattatt tcaactaagc aatatgttga agtgttgagc cgcatattta aaaattctga 9420 gggcaaacaa ttagatccta atgaaatgcg tacagttaag agagtagttt ctggtctgtt 9480 caggagtcta cagaatgatt cagtcaaggt gaggagtgat ctcgagaatg tacgagacct 9540 tgcgctttac ctcccaagcc aggatggtag attggtaaag tcaagcatct tagtgtttga 9600 cgatgcgcca cattataaaa gtagaatcca ggggaatatt ggtgtgcaaa tgttagttga 9660 tctcagccag tgctacttag ggaaagacca tggatttcac actaagttga taatgctctt 9720 tcctcaaaaa cttagacctc gattattgag cagtatactt gaagaacaat tagatgaaga 9780 gactcccaaa gtttgtcagt ttggagcgtt gtgttctctt caaggaagat tgcagttact 9840 cttgtcttct gaacagttca ttacaggact gattagaatt atgaagcatg aaaatgataa 9900 tgcttttctg gccaatgaag aaaaagccat aagactttgc aaagccctaa gagaaggatt 9960 gaaagtatcc tgctttgaaa agcttcaaac aacattaaga gttaaaggtt ttaatcctat 10020 tccccacagc agaagtgaaa cttttgcttt tttgaagcga tttggtaatg cagtcatctt 10080 gctctacatt caacattcag acagtaaaga cattaatttc ctgttagcac tggcaatgac 10140 tcttaaatca gcaactgaca atttgatttc tgacacttca tatttaattg ctatgctagg 10200 atgcaatgat atttacagga ttggtgagaa acttgacagt ttaggagtga aatatgactc 10260 ttcggagcca tcaaaactgg aacttccaat gcctggcaca ccaattcctg ctgaaattca 10320 ttacactctg cttatggacc caatgaatgt tttttacccg ggagaatatg ttgggtacct 10380 tgttgatgct gaaggtggtg atatctatgg atcataccag ccaacataca catatgcaat 10440 tattgtacaa gaagttgaaa gagaagatgc tgacaattct agttttctag gaaagatata 10500 tcagatagat attggttata gtgaatataa aatagttagc tctcttgatc tgtataagtt 10560 ttcaagacct gaggaaagct ctcaaagcag ggacagtgct ccttctacac caaccagccc 10620 cactgagttc ctcacccctg gcctgagaag cattcctcct cttttctctg gtagagagag 10680 ccacaagact tcttccaaac atcagtcccc caaaaagctt aaggttaatt ctttaccaga 10740 aatcttaaaa gaagtgacat ctgtggtgga gcaagcatgg aagcttccag aatcggaacg 10800 aaaaaagatt attaggcggt tgtatttgaa atggcatcct gacaaaaatc cagagaacca 10860 tgacattgcc aatgaagttt ttaaacattt gcagaatgaa atcaacagat tagaaaaaca 10920 ggcttttcta gatcaaaatg cagacagggc ctccagacga acattttcaa cctcagcatc 10980 ccgatttcag tcagacaaat actcatttca gagattctat acttcatgga atcaagaagc 11040 aacgagccat aaatctgaaa gacagcaaca gaacaaagaa aaatgccccc cttcagccgg 11100 acagacttac tctcaaaggt tctttgttcc tcccactttc aagtcggttg gcaatccagt 11160 ggaagcacgc agatggctaa gacaagccag agcaaacttc tcagctgcca ggaatgacct 11220 tcataaaaat gccaatgagt gggtgtgctt taaatgttac ctttctacca agttagcttt 11280 gattgcagct gactatgctg tgaggggaaa gtctgataaa gatgtaaaac caactgcact 11340 tgctcagaaa atagaggaat atagtcagca acttgaagga ctgacaaatg atgttcacac 11400 attggaagct tatggtgtag acagtttaaa aacaagatac cctgatttgc ttccctttcc 11460 tcagatccca aatgacaggt tcacttctga ggttgctatg agggtgatgg aatgtactgc 11520 ctgtatcata ataaaacttg aaaattttat gcaacaaaaa gtgtgaagat atttaacgaa 11580 aaaaaaggta gatcttgaat gtgttgtagc acgaataaat tgctgtactt cattaagctt 11640 cattgccaat tagctaggaa ttgttaagca cattgcagat tgttcttgga gaattctgga 11700 gttgttatga acatgaatac caacggaaaa ccttaactga atctaaaaga aaactatttt 11760 gaagatggtg gtgagctgca aaatagctgg atggatttga atgattggga tgatacatca 11820 ttgaactgca ctttatataa ccaaagctta gcagtttgtt agataagagt ctatgtatgt 11880 ctctggttag gatgaagtta attttatgtt tttaacatgg tatttttgaa ggagctaatg 11940 aaacactgga catataattg gtttaaacat aaggggaatt aagtctttgt agtctgtcat 12000 ttttttaagt ggatcctctt ggatgcgtta ttttctcatc agctggctct gatcatgaat 12060 ttgttgtaat tttatgttgt actcagtgca tttaagaaat ggtagagtat tttaatccta 12120 ttacttgact aagagtgtga aggtagtact ttttagagtg cactgagtgc actttacatc 12180 tttatttaaa ttttttttta acatcttatg tttacaggct tcctgtttga tgaagatagc 12240 aacggaaaac tcaaaatggt ggcagttctt attaccagtt gttagtattg tttctggaaa 12300 ctgcttgcca agacaacatt tattaactgt tagaacactt gctttatgtt tgtgtgtaca 12360 tattttccac aaatgttata atttatatag tgtggttgaa caggatgcaa tcttttgttg 12420 tctaaaggtg ctgcagttaa aaaaaaaaca accttttctt tcaatatggc atgtagtgga 12480 gtttttttaa ctttaaaaac atcaaaaatt gttaaaatca ttgtgttatc tagtagttta 12540 taattatcgg cttatatttc cccatgaatg atcagaactg acatttaatt catgtttgtc 12600 tcgccatgct tctttacttt aacatatttc ttttgcagaa tgtaaaaggt aatgataatt 12660 agtttatata agtgtactgg ctgtaaatga tgctaaatat actttatgca attaagggct 12720 tacagaacat gttgaaactt tttttacttt tattgggaat aaggaatgtt tgcacctcca 12780 cattttattg ctt 12793 <210> SEQ ID NO 2 <211> LENGTH: 3829 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 2 Met Asn Thr Phe Trp Pro Gly Arg Glu Leu Ile Val Gln Trp Tyr Pro 1 5 10 15 Phe Asp Glu Asn Arg Asn His Pro Ser Val Ser Trp Leu Lys Met Val 20 25 30 Trp Lys Asn Leu Tyr Ile His Phe Ser Glu Asp Leu Thr Leu Phe Asp 35 40 45 Glu Met Pro Leu Ile Pro Arg Thr Ile Leu Glu Glu Gly Gln Thr Cys 50 55 60 Val Glu Leu Ile Arg Leu Arg Ile Pro Ser Leu Val Ile Leu Asp Asp 65 70 75 80 Glu Ser Glu Ala Gln Leu Pro Glu Phe Leu Ala Asp Ile Val Gln Lys 85 90 95 Leu Gly Gly Phe Val Leu Lys Lys Leu Asp Ala Ser Ile Gln His Pro 100 105 110 Leu Ile Lys Lys Tyr Ile His Ser Pro Leu Pro Ser Ala Val Leu Gln 115 120 125 Ile Met Glu Lys Met Pro Leu Gln Lys Leu Cys Asn Gln Ile Thr Ser 130 135 140 Leu Leu Pro Thr His Lys Asp Ala Leu Arg Lys Phe Leu Ala Ser Leu 145 150 155 160 Thr Asp Ser Ser Glu Lys Glu Lys Arg Ile Ile Gln Glu Leu Ala Ile 165 170 175 Phe Lys Arg Ile Asn His Ser Ser Asp Gln Gly Ile Ser Ser Tyr Thr 180 185 190 Lys Leu Lys Gly Cys Lys Val Leu His His Thr Ala Lys Leu Pro Ala 195 200 205 Asp Leu Arg Leu Ser Ile Ser Val Ile Asp Ser Ser Asp Glu Ala Thr 210 215 220 Ile Arg Leu Ala Asn Met Leu Lys Ile Glu Gln Leu Lys Thr Thr Ser 225 230 235 240 Cys Leu Lys Leu Val Leu Lys Asp Ile Glu Asn Ala Phe Tyr Ser His 245 250 255 Glu Glu Val Thr Gln Leu Met Leu Trp Val Leu Glu Asn Leu Ser Ser 260 265 270 Leu Lys Asn Glu Asn Pro Asn Val Leu Glu Trp Leu Thr Pro Leu Lys 275 280 285 Phe Ile Gln Ile Ser Gln Glu Gln Met Val Ser Ala Gly Glu Leu Phe 290 295 300 Asp Pro Asp Ile Glu Val Leu Lys Asp Leu Phe Cys Asn Glu Glu Gly 305 310 315 320 Thr Tyr Phe Pro Pro Ser Val Phe Thr Ser Pro Asp Ile Leu His Ser 325 330 335 Leu Arg Gln Ile Gly Leu Lys Asn Glu Ala Ser Leu Lys Glu Lys Asp 340 345 350 Val Val Gln Val Ala Lys Lys Ile Glu Ala Leu Gln Val Gly Ala Cys 355 360 365 Pro Asp Gln Asp Val Leu Leu Lys Lys Ala Lys Thr Leu Leu Leu Val 370 375 380 Leu Asn Lys Asn His Thr Leu Leu Gln Ser Ser Glu Gly Lys Met Thr 385 390 395 400 Leu Lys Lys Ile Lys Trp Val Pro Ala Cys Lys Glu Arg Pro Pro Asn 405 410 415 Tyr Pro Gly Ser Leu Val Trp Lys Gly Asp Leu Cys Asn Leu Cys Ala 420 425 430 Pro Pro Asp Met Cys Asp Val Gly His Ala Ile Leu Ile Gly Ser Ser 435 440 445 Leu Pro Leu Val Glu Ser Ile His Val Asn Leu Glu Lys Ala Leu Gly 450 455 460 Ile Phe Thr Lys Pro Ser Leu Ser Ala Val Leu Lys His Phe Lys Ile 465 470 475 480 Val Val Asp Trp Tyr Ser Ser Lys Thr Phe Ser Asp Glu Asp Tyr Tyr 485 490 495 Gln Phe Gln His Ile Leu Leu Glu Ile Tyr Gly Phe Met His Asp His 500 505 510 Leu Asn Glu Gly Lys Asp Ser Phe Arg Ala Leu Lys Phe Pro Trp Val 515 520 525 Trp Thr Gly Lys Lys Phe Cys Pro Leu Ala Gln Ala Val Ile Lys Pro 530 535 540 Ile His Asp Leu Asp Leu Gln Pro Tyr Leu His Asn Val Pro Lys Thr 545 550 555 560 Met Ala Lys Phe His Gln Leu Phe Lys Val Cys Gly Ser Ile Glu Glu 565 570 575 Leu Thr Ser Asp His Ile Ser Met Val Ile Gln Lys Ile Tyr Leu Lys 580 585 590 Ser Asp Gln Asp Leu Ser Glu Gln Glu Ser Lys Gln Asn Leu His Leu 595 600 605 Met Leu Asn Ile Ile Arg Trp Leu Tyr Ser Asn Gln Ile Pro Ala Ser 610 615 620 Pro Asn Thr Pro Val Pro Ile His His Ser Lys Asn Pro Ser Lys Leu 625 630 635 640 Ile Met Lys Pro Ile His Glu Cys Cys Tyr Cys Asp Ile Lys Val Asp 645 650 655 Asp Leu Asn Asp Leu Leu Glu Asp Ser Val Glu Pro Ile Ile Leu Val 660 665 670 His Glu Asp Ile Pro Met Lys Thr Ala Glu Trp Leu Lys Val Pro Cys 675 680 685 Leu Ser Thr Arg Leu Ile Asn Pro Glu Asn Met Gly Phe Glu Gln Ser 690 695 700 Gly Gln Arg Glu Pro Leu Thr Val Arg Ile Lys Asn Ile Leu Glu Glu 705 710 715 720 Tyr Pro Ser Val Ser Asp Ile Phe Lys Glu Leu Leu Gln Asn Ala Asp 725 730 735 Asp Ala Asn Ala Thr Glu Cys Ser Phe Leu Ile Asp Met Arg Arg Asn 740 745 750 Met Asp Ile Arg Glu Asn Leu Leu Asp Pro Gly Met Ala Ala Cys His 755 760 765 Gly Pro Ala Leu Trp Ser Phe Asn Asn Ser Gln Phe Ser Asp Ser Asp 770 775 780 Phe Val Asn Ile Thr Arg Leu Gly Glu Ser Leu Lys Arg Gly Glu Val 785 790 795 800 Asp Lys Val Gly Lys Phe Gly Leu Gly Phe Asn Ser Val Tyr His Ile 805 810 815 Thr Asp Ile Pro Ile Ile Met Ser Arg Glu Phe Met Ile Met Phe Asp 820 825 830 Pro Asn Ile Asn His Ile Ser Lys His Ile Lys Asp Lys Ser Asn Pro 835 840 845 Gly Ile Lys Ile Asn Trp Ser Lys Gln Gln Lys Arg Leu Arg Lys Phe 850 855 860 Pro Asn Gln Phe Lys Pro Phe Ile Asp Val Phe Gly Cys Gln Leu Pro 865 870 875 880 Leu Thr Val Glu Ala Pro Tyr Ser Tyr Asn Gly Thr Leu Phe Arg Leu 885 890 895 Ser Phe Arg Thr Gln Gln Glu Ala Lys Val Ser Glu Val Ser Ser Thr 900 905 910 Cys Tyr Asn Thr Ala Asp Ile Tyr Ser Leu Val Asp Glu Phe Ser Leu 915 920 925 Cys Gly His Arg Leu Ile Ile Phe Thr Gln Ser Val Lys Ser Met Tyr 930 935 940 Leu Lys Tyr Leu Lys Ile Glu Glu Thr Asn Pro Ser Leu Ala Gln Asp 945 950 955 960 Thr Val Ile Ile Lys Lys Lys Ser Cys Ser Ser Lys Ala Leu Asn Thr 965 970 975 Pro Val Leu Ser Val Leu Lys Glu Ala Ala Lys Leu Met Lys Thr Cys 980 985 990 Ser Ser Ser Asn Lys Lys Leu Pro Ser Asp Glu Pro Lys Ser Ser Cys 995 1000 1005 Ile Leu Gln Ile Thr Val Glu Glu Phe His His Val Phe Arg Arg Ile 1010 1015 1020 Ala Asp Leu Gln Ser Pro Leu Phe Arg Gly Pro Asp Asp Asp Pro Ala 1025 1030 1035 1040 Ala Leu Phe Glu Met Ala Lys Ser Gly Gln Ser Lys Lys Pro Ser Asp 1045 1050 1055 Glu Leu Ser Gln Lys Thr Val Glu Cys Thr Thr Trp Leu Leu Cys Thr 1060 1065 1070 Cys Met Asp Thr Gly Glu Ala Leu Lys Phe Ser Leu Ser Glu Ser Gly 1075 1080 1085 Arg Arg Leu Gly Leu Val Pro Cys Gly Ala Val Gly Val Gln Leu Ser 1090 1095 1100 Glu Ile Gln Asp Gln Lys Trp Thr Val Lys Pro His Ile Gly Glu Val 1105 1110 1115 1120 Phe Cys Tyr Leu Pro Leu Arg Ile Lys Thr Gly Leu Pro Val His Ile 1125 1130 1135 Asn Gly Cys Phe Ala Val Thr Ser Asn Arg Lys Glu Ile Trp Lys Thr 1140 1145 1150 Asp Thr Lys Gly Arg Trp Asn Thr Thr Phe Met Arg His Val Ile Val 1155 1160 1165 Lys Ala Tyr Leu Gln Val Leu Ser Val Leu Arg Asp Leu Ala Thr Ser 1170 1175 1180 Gly Glu Leu Met Asp Tyr Thr Tyr Tyr Ala Val Trp Pro Asp Pro Asp 1185 1190 1195 1200 Leu Val His Asp Asp Phe Ser Val Ile Cys Gln Gly Phe Tyr Glu Asp 1205 1210 1215 Ile Ala His Gly Lys Gly Lys Glu Leu Thr Lys Val Phe Ser Asp Gly 1220 1225 1230 Ser Thr Trp Val Ser Met Lys Asn Val Arg Phe Leu Asp Asp Ser Ile 1235 1240 1245 Leu Lys Arg Arg Asp Val Gly Ser Ala Ala Phe Lys Ile Phe Leu Lys 1250 1255 1260 Tyr Leu Lys Lys Thr Gly Ser Lys Asn Leu Cys Ala Val Glu Leu Pro 1265 1270 1275 1280 Ser Ser Val Lys Leu Gly Phe Glu Glu Ala Gly Cys Lys Gln Ile Leu 1285 1290 1295 Leu Glu Asn Thr Phe Ser Glu Lys Gln Phe Phe Ser Glu Val Phe Phe 1300 1305 1310 Pro Asn Ile Gln Glu Ile Glu Ala Glu Leu Arg Asp Pro Leu Met Ile 1315 1320 1325 Phe Val Leu Asn Glu Lys Val Asp Glu Phe Ser Gly Val Leu Arg Val 1330 1335 1340 Thr Pro Cys Ile Pro Cys Ser Leu Glu Gly His Pro Leu Val Leu Pro 1345 1350 1355 1360 Ser Arg Leu Ile His Pro Glu Gly Arg Val Ala Lys Leu Phe Asp Ile 1365 1370 1375 Lys Asp Gly Arg Phe Pro Tyr Gly Ser Thr Gln Asp Tyr Leu Asn Pro 1380 1385 1390 Ile Ile Leu Ile Lys Leu Val Gln Leu Gly Lys Ala Lys Asp Asp Ile 1395 1400 1405 Leu Trp Asp Asp Met Leu Glu Arg Ala Val Ser Val Ala Glu Ile Asn 1410 1415 1420 Lys Ser Asp His Val Ala Ala Cys Leu Arg Ser Ser Ile Leu Leu Ser 1425 1430 1435 1440 Leu Ile Asp Glu Lys Leu Lys Ile Arg Asp Pro Arg Ala Lys Asp Phe 1445 1450 1455 Ala Ala Lys Tyr Gln Thr Ile Arg Phe Leu Pro Phe Leu Thr Lys Pro 1460 1465 1470 Ala Gly Phe Ser Leu Asp Trp Lys Gly Asn Ser Phe Lys Pro Glu Thr 1475 1480 1485 Met Phe Ala Ala Thr Asp Leu Tyr Thr Ala Glu His Gln Asp Ile Val 1490 1495 1500 Cys Leu Leu Gln Pro Ile Leu Asn Glu Asn Ser His Ser Phe Arg Gly 1505 1510 1515 1520 Cys Gly Ser Val Ser Leu Ala Val Lys Glu Phe Leu Gly Leu Leu Lys 1525 1530 1535 Lys Pro Thr Val Asp Leu Val Ile Asn Gln Leu Lys Glu Val Ala Lys 1540 1545 1550 Ser Val Asp Asp Gly Ile Thr Leu Tyr Gln Glu Asn Ile Thr Asn Ala 1555 1560 1565 Cys Tyr Lys Tyr Leu His Glu Ala Leu Met Gln Asn Glu Ile Thr Lys 1570 1575 1580 Met Ser Ile Ile Asp Lys Leu Lys Pro Phe Ser Phe Ile Leu Val Glu 1585 1590 1595 1600 Asn Ala Tyr Val Asp Ser Glu Lys Val Ser Phe His Leu Asn Phe Glu 1605 1610 1615 Ala Ala Pro Tyr Leu Tyr Gln Leu Pro Asn Lys Tyr Lys Asn Asn Phe 1620 1625 1630 Arg Glu Leu Phe Glu Thr Val Gly Val Arg Gln Ser Cys Thr Val Glu 1635 1640 1645 Asp Phe Ala Leu Val Leu Glu Ser Ile Asp Gln Glu Arg Gly Thr Lys 1650 1655 1660 Gln Ile Thr Glu Glu Asn Phe Gln Leu Cys Arg Arg Ile Ile Ser Glu 1665 1670 1675 1680 Gly Ile Trp Ser Leu Ile Arg Glu Lys Lys Gln Glu Phe Cys Glu Lys 1685 1690 1695 Asn Tyr Gly Lys Ile Leu Leu Pro Asp Thr Asn Leu Met Leu Leu Pro 1700 1705 1710 Ala Lys Ser Leu Cys Tyr Asn Asp Cys Pro Trp Ile Lys Val Lys Asp 1715 1720 1725 Thr Thr Val Lys Tyr Cys His Ala Asp Ile Pro Arg Glu Val Ala Val 1730 1735 1740 Lys Leu Gly Ala Val Pro Lys Arg His Lys Ala Leu Glu Arg Tyr Ala 1745 1750 1755 1760 Ser Asn Val Cys Phe Thr Thr Leu Gly Thr Glu Phe Gly Gln Lys Glu 1765 1770 1775 Lys Leu Thr Ser Arg Ile Lys Ser Ile Leu Asn Ala Tyr Pro Ser Glu 1780 1785 1790 Lys Glu Met Leu Lys Glu Leu Leu Gln Asn Ala Asp Asp Ala Lys Ala 1795 1800 1805 Thr Glu Ile Cys Phe Val Phe Asp Pro Arg Gln His Pro Val Asp Arg 1810 1815 1820 Ile Phe Asp Asp Lys Trp Ala Pro Leu Gln Gly Pro Ala Leu Cys Val 1825 1830 1835 1840 Tyr Asn Asn Gln Pro Phe Thr Glu Asp Asp Val Arg Gly Ile Gln Asn 1845 1850 1855 Leu Gly Lys Gly Thr Lys Glu Gly Asn Pro Tyr Lys Thr Gly Gln Tyr 1860 1865 1870 Gly Ile Gly Phe Asn Ser Val Tyr His Ile Thr Asp Cys Pro Ser Phe 1875 1880 1885 Ile Ser Gly Asn Asp Ile Leu Cys Ile Phe Asp Pro His Ala Arg Tyr 1890 1895 1900 Ala Pro Gly Ala Thr Ser Ile Ser Pro Gly Arg Met Phe Arg Asp Leu 1905 1910 1915 1920 Asp Ala Asp Phe Arg Thr Gln Phe Ser Asp Val Leu Asp Leu Tyr Leu 1925 1930 1935 Gly Thr His Phe Lys Leu Asp Asn Cys Thr Met Phe Arg Phe Pro Leu 1940 1945 1950 Arg Asn Ala Glu Met Ala Lys Val Ser Glu Ile Ser Ser Val Pro Ala 1955 1960 1965 Ser Asp Arg Met Val Gln Asn Leu Leu Asp Lys Leu Arg Ser Asp Gly 1970 1975 1980 Ala Glu Leu Leu Met Phe Leu Asn His Met Glu Lys Ile Ser Ile Cys 1985 1990 1995 2000 Glu Ile Asp Lys Ser Thr Gly Ala Leu Asn Val Leu Tyr Ser Val Lys 2005 2010 2015 Gly Lys Ile Thr Asp Gly Asp Arg Leu Lys Arg Lys Gln Phe His Ala 2020 2025 2030 Ser Val Ile Asp Ser Val Thr Lys Lys Arg Gln Leu Lys Asp Ile Pro 2035 2040 2045 Val Gln Gln Ile Thr Tyr Thr Met Asp Thr Glu Asp Ser Glu Gly Asn 2050 2055 2060 Leu Thr Thr Trp Leu Ile Cys Asn Arg Ser Gly Phe Ser Ser Met Glu 2065 2070 2075 2080 Lys Val Ser Lys Ser Val Ile Ser Ala His Lys Asn Gln Asp Ile Thr 2085 2090 2095 Leu Phe Pro Arg Gly Gly Val Ala Ala Cys Ile Thr His Asn Tyr Lys 2100 2105 2110 Lys Pro His Arg Ala Phe Cys Phe Leu Pro Leu Ser Leu Glu Thr Gly 2115 2120 2125 Leu Pro Phe His Val Asn Gly His Phe Ala Leu Asp Ser Ala Arg Arg 2130 2135 2140 Asn Leu Trp Arg Asp Asp Asn Gly Val Gly Val Arg Ser Asp Trp Asn 2145 2150 2155 2160 Asn Ser Leu Met Thr Ala Leu Ile Ala Pro Ala Tyr Val Glu Leu Leu 2165 2170 2175 Ile Gln Leu Lys Lys Arg Tyr Phe Pro Gly Ser Asp Pro Thr Leu Ser 2180 2185 2190 Val Leu Gln Asn Thr Pro Ile His Val Val Lys Asp Thr Leu Lys Lys 2195 2200 2205 Phe Leu Ser Phe Phe Pro Val Asn Arg Leu Asp Leu Gln Pro Asp Leu 2210 2215 2220 Tyr Cys Leu Val Lys Ala Leu Tyr Asn Cys Ile His Glu Asp Met Lys 2225 2230 2235 2240 Arg Leu Leu Pro Val Val Arg Ala Pro Asn Ile Asp Gly Ser Asp Leu 2245 2250 2255 His Ser Ala Val Ile Ile Thr Trp Ile Asn Met Ser Thr Ser Asn Lys 2260 2265 2270 Thr Arg Pro Phe Phe Asp Asn Leu Leu Gln Asp Glu Leu Gln His Leu 2275 2280 2285 Lys Asn Ala Asp Tyr Asn Ile Thr Thr Arg Lys Thr Val Ala Glu Asn 2290 2295 2300 Val Tyr Arg Leu Lys His Leu Leu Leu Glu Ile Gly Phe Asn Leu Val 2305 2310 2315 2320 Tyr Asn Cys Asp Glu Thr Ala Asn Leu Tyr His Cys Leu Ile Asp Ala 2325 2330 2335 Asp Ile Pro Val Ser Tyr Val Thr Pro Ala Asp Ile Arg Ser Phe Leu 2340 2345 2350 Met Thr Phe Ser Ser Pro Asp Thr Asn Cys His Ile Gly Lys Leu Pro 2355 2360 2365 Cys Arg Leu Gln Gln Thr Asn Leu Lys Leu Phe His Ser Leu Lys Leu 2370 2375 2380 Leu Val Asp Tyr Cys Phe Lys Asp Ala Glu Glu Asn Glu Ile Glu Val 2385 2390 2395 2400 Glu Gly Leu Pro Leu Leu Ile Thr Leu Asp Ser Val Leu Gln Thr Phe 2405 2410 2415 Asp Ala Lys Arg Pro Lys Phe Leu Thr Thr Tyr His Glu Leu Ile Pro 2420 2425 2430 Ser Arg Lys Asp Leu Phe Met Asn Thr Leu Tyr Leu Lys Tyr Ser Asn 2435 2440 2445 Ile Leu Leu Asn Cys Lys Val Ala Lys Val Phe Asp Ile Ser Ser Phe 2450 2455 2460 Ala Asp Leu Leu Ser Ser Val Leu Pro Arg Glu Tyr Lys Thr Lys Ser 2465 2470 2475 2480 Cys Thr Lys Trp Lys Asp Asn Phe Ala Ser Glu Ser Trp Leu Lys Asn 2485 2490 2495 Ala Trp His Phe Ile Ser Glu Ser Val Ser Val Lys Glu Asp Gln Glu 2500 2505 2510 Glu Thr Lys Pro Thr Phe Asp Ile Val Val Asp Thr Leu Lys Asp Trp 2515 2520 2525 Ala Leu Leu Pro Gly Thr Lys Phe Thr Val Ser Ala Asn Gln Leu Val 2530 2535 2540 Val Pro Glu Gly Asp Val Leu Leu Pro Leu Ser Leu Met His Ile Ala 2545 2550 2555 2560 Val Phe Pro Asn Ala Gln Ser Asp Lys Val Phe His Ala Leu Met Lys 2565 2570 2575 Ala Gly Cys Ile Gln Leu Ala Leu Asn Lys Ile Cys Ser Lys Asp Ser 2580 2585 2590 Ala Phe Val Pro Leu Leu Ser Cys His Thr Ala Asn Ile Glu Ser Pro 2595 2600 2605 Thr Ser Ile Leu Lys Ala Leu His Tyr Met Val Gln Thr Ser Thr Phe 2610 2615 2620 Arg Ala Glu Lys Leu Val Glu Asn Asp Phe Glu Ala Leu Leu Met Tyr 2625 2630 2635 2640 Phe Asn Cys Asn Leu Asn His Leu Met Ser Gln Asp Asp Ile Lys Ile 2645 2650 2655 Leu Lys Ser Leu Pro Cys Tyr Lys Ser Ile Ser Gly Arg Tyr Val Ser 2660 2665 2670 Ile Gly Lys Phe Gly Thr Cys Tyr Val Leu Thr Lys Ser Ile Pro Ser 2675 2680 2685 Ala Glu Val Glu Lys Trp Thr Gln Ser Ser Ser Ser Ala Phe Leu Glu 2690 2695 2700 Glu Lys Ile His Leu Lys Glu Leu Tyr Glu Val Ile Gly Cys Val Pro 2705 2710 2715 2720 Val Asp Asp Leu Glu Val Tyr Leu Lys His Leu Leu Pro Lys Ile Glu 2725 2730 2735 Asn Leu Ser Tyr Asp Ala Lys Leu Glu His Leu Ile Tyr Leu Lys Asn 2740 2745 2750 Arg Leu Ser Ser Ala Glu Glu Leu Ser Glu Ile Lys Glu Gln Leu Phe 2755 2760 2765 Glu Lys Leu Glu Ser Leu Leu Ile Ile His Asp Ala Asn Ser Arg Leu 2770 2775 2780 Lys Gln Ala Lys His Phe Tyr Asp Arg Thr Val Arg Val Phe Glu Val 2785 2790 2795 2800 Met Leu Pro Glu Lys Leu Phe Ile Pro Asn Asp Phe Phe Lys Lys Leu 2805 2810 2815 Glu Gln Leu Ile Lys Pro Lys Asn His Val Thr Phe Met Thr Ser Trp 2820 2825 2830 Val Glu Phe Leu Arg Asn Ile Gly Leu Lys Tyr Ile Leu Ser Gln Gln 2835 2840 2845 Gln Leu Leu Gln Phe Ala Lys Glu Ile Ser Val Arg Ala Asn Thr Glu 2850 2855 2860 Asn Trp Ser Lys Glu Thr Leu Gln Asn Thr Val Asp Ile Leu Leu His 2865 2870 2875 2880 His Ile Phe Gln Glu Arg Met Asp Leu Leu Ser Gly Asn Phe Leu Lys 2885 2890 2895 Glu Leu Ser Leu Ile Pro Phe Leu Cys Pro Glu Arg Ala Pro Ala Glu 2900 2905 2910 Phe Ile Arg Phe His Pro Gln Tyr Gln Glu Val Asn Gly Thr Leu Pro 2915 2920 2925 Leu Ile Lys Phe Asn Gly Ala Gln Val Asn Pro Lys Phe Lys Gln Cys 2930 2935 2940 Asp Val Leu Gln Leu Leu Trp Thr Ser Cys Pro Ile Leu Pro Glu Lys 2945 2950 2955 2960 Ala Thr Pro Leu Ser Ile Lys Glu Gln Glu Gly Ser Asp Leu Gly Pro 2965 2970 2975 Gln Glu Gln Leu Glu Gln Val Leu Asn Met Leu Asn Val Asn Leu Asp 2980 2985 2990 Pro Pro Leu Asp Lys Val Ile Asn Asn Cys Arg Asn Ile Cys Asn Ile 2995 3000 3005 Thr Thr Leu Asp Glu Glu Met Val Lys Thr Arg Ala Lys Val Leu Arg 3010 3015 3020 Ser Ile Tyr Glu Phe Leu Ser Ala Glu Lys Arg Glu Phe Arg Phe Gln 3025 3030 3035 3040 Leu Arg Gly Val Ala Phe Val Met Val Glu Asp Gly Trp Lys Leu Leu 3045 3050 3055 Lys Pro Glu Glu Val Val Ile Asn Leu Glu Tyr Glu Ser Asp Phe Lys 3060 3065 3070 Pro Tyr Leu Tyr Lys Leu Pro Leu Glu Leu Gly Thr Phe His Gln Leu 3075 3080 3085 Phe Lys His Leu Gly Thr Glu Asp Ile Ile Ser Thr Lys Gln Tyr Val 3090 3095 3100 Glu Val Leu Ser Arg Ile Phe Lys Asn Ser Glu Gly Lys Gln Leu Asp 3105 3110 3115 3120 Pro Asn Glu Met Arg Thr Val Lys Arg Val Val Ser Gly Leu Phe Arg 3125 3130 3135 Ser Leu Gln Asn Asp Ser Val Lys Val Arg Ser Asp Leu Glu Asn Val 3140 3145 3150 Arg Asp Leu Ala Leu Tyr Leu Pro Ser Gln Asp Gly Arg Leu Val Lys 3155 3160 3165 Ser Ser Ile Leu Val Phe Asp Asp Ala Pro His Tyr Lys Ser Arg Ile 3170 3175 3180 Gln Gly Asn Ile Gly Val Gln Met Leu Val Asp Leu Ser Gln Cys Tyr 3185 3190 3195 3200 Leu Gly Lys Asp His Gly Phe His Thr Lys Leu Ile Met Leu Phe Pro 3205 3210 3215 Gln Lys Leu Arg Pro Arg Leu Leu Ser Ser Ile Leu Glu Glu Gln Leu 3220 3225 3230 Asp Glu Glu Thr Pro Lys Val Cys Gln Phe Gly Ala Leu Cys Ser Leu 3235 3240 3245 Gln Gly Arg Leu Gln Leu Leu Leu Ser Ser Glu Gln Phe Ile Thr Gly 3250 3255 3260 Leu Ile Arg Ile Met Lys His Glu Asn Asp Asn Ala Phe Leu Ala Asn 3265 3270 3275 3280 Glu Glu Lys Ala Ile Arg Leu Cys Lys Ala Leu Arg Glu Gly Leu Lys 3285 3290 3295 Val Ser Cys Phe Glu Lys Leu Gln Thr Thr Leu Arg Val Lys Gly Phe 3300 3305 3310 Asn Pro Ile Pro His Ser Arg Ser Glu Thr Phe Ala Phe Leu Lys Arg 3315 3320 3325 Phe Gly Asn Ala Val Ile Leu Leu Tyr Ile Gln His Ser Asp Ser Lys 3330 3335 3340 Asp Ile Asn Phe Leu Leu Ala Leu Ala Met Thr Leu Lys Ser Ala Thr 3345 3350 3355 3360 Asp Asn Leu Ile Ser Asp Thr Ser Tyr Leu Ile Ala Met Leu Gly Cys 3365 3370 3375 Asn Asp Ile Tyr Arg Ile Gly Glu Lys Leu Asp Ser Leu Gly Val Lys 3380 3385 3390 Tyr Asp Ser Ser Glu Pro Ser Lys Leu Glu Leu Pro Met Pro Gly Thr 3395 3400 3405 Pro Ile Pro Ala Glu Ile His Tyr Thr Leu Leu Met Asp Pro Met Asn 3410 3415 3420 Val Phe Tyr Pro Gly Glu Tyr Val Gly Tyr Leu Val Asp Ala Glu Gly 3425 3430 3435 3440 Gly Asp Ile Tyr Gly Ser Tyr Gln Pro Thr Tyr Thr Tyr Ala Ile Ile 3445 3450 3455 Val Gln Glu Val Glu Arg Glu Asp Ala Asp Asn Ser Ser Phe Leu Gly 3460 3465 3470 Lys Ile Tyr Gln Ile Asp Ile Gly Tyr Ser Glu Tyr Lys Ile Val Ser 3475 3480 3485 Ser Leu Asp Leu Tyr Lys Phe Ser Arg Pro Glu Glu Ser Ser Gln Ser 3490 3495 3500 Arg Asp Ser Ala Pro Ser Thr Pro Thr Ser Pro Thr Glu Phe Leu Thr 3505 3510 3515 3520 Pro Gly Leu Arg Ser Ile Pro Pro Leu Phe Ser Gly Arg Glu Ser His 3525 3530 3535 Lys Thr Ser Ser Lys His Gln Ser Pro Lys Lys Leu Lys Val Asn Ser 3540 3545 3550 Leu Pro Glu Ile Leu Lys Glu Val Thr Ser Val Val Glu Gln Ala Trp 3555 3560 3565 Lys Leu Pro Glu Ser Glu Arg Lys Lys Ile Ile Arg Arg Leu Tyr Leu 3570 3575 3580 Lys Trp His Pro Asp Lys Asn Pro Glu Asn His Asp Ile Ala Asn Glu 3585 3590 3595 3600 Val Phe Lys His Leu Gln Asn Glu Ile Asn Arg Leu Glu Lys Gln Ala 3605 3610 3615 Phe Leu Asp Gln Asn Ala Asp Arg Ala Ser Arg Arg Thr Phe Ser Thr 3620 3625 3630 Ser Ala Ser Arg Phe Gln Ser Asp Lys Tyr Ser Phe Gln Arg Phe Tyr 3635 3640 3645 Thr Ser Trp Asn Gln Glu Ala Thr Ser His Lys Ser Glu Arg Gln Gln 3650 3655 3660 Gln Asn Lys Glu Lys Cys Pro Pro Ser Ala Gly Gln Thr Tyr Ser Gln 3665 3670 3675 3680 Arg Phe Phe Val Pro Pro Thr Phe Lys Ser Val Gly Asn Pro Val Glu 3685 3690 3695 Ala Arg Arg Trp Leu Arg Gln Ala Arg Ala Asn Phe Ser Ala Ala Arg 3700 3705 3710 Asn Asp Leu His Lys Asn Ala Asn Glu Trp Val Cys Phe Lys Cys Tyr 3715 3720 3725 Leu Ser Thr Lys Leu Ala Leu Ile Ala Ala Asp Tyr Ala Val Arg Gly 3730 3735 3740 Lys Ser Asp Lys Asp Val Lys Pro Thr Ala Leu Ala Gln Lys Ile Glu 3745 3750 3755 3760 Glu Tyr Ser Gln Gln Leu Glu Gly Leu Thr Asn Asp Val His Thr Leu 3765 3770 3775 Glu Ala Tyr Gly Val Asp Ser Leu Lys Thr Arg Tyr Pro Asp Leu Leu 3780 3785 3790 Pro Phe Pro Gln Ile Pro Asn Asp Arg Phe Thr Ser Glu Val Ala Met 3795 3800 3805 Arg Val Met Glu Cys Thr Ala Cys Ile Ile Ile Lys Leu Glu Asn Phe 3810 3815 3820 Met Gln Gln Lys Val 3825 <210> SEQ ID NO 3 <211> LENGTH: 11492 <212> TYPE: DNA <213> ORGANISM: Mus musculus <400> SEQUENCE: 3 atgaatacat tctggcctgg tcgagagttg gtggttcagt ggtatccatt tagtgaagac 60 aaacgtcacc catccctttc atggcttaag atggtttgga agaatctcta tatacatttc 120 tcggaagatt tgactttatt tgatgagatg ccacttatcc ctagaactct actgaatgag 180 gaccagacgt gtgtggaact catcagactc aggatcccat cagtagtcat tttagatgat 240 gaaactgaag ctcagcttcc agaattctta gcagatattg tacaaaaact tggagggatt 300 gtcctgaaaa gactagatac ctctattcag catccacttg ttaaaaaata cattcattcc 360 ccactcccga gtgctatttt gcagataatg gagaagatac ctctacagaa gttgtgtaat 420 aaatagcatc attacttcca acccacaaag atgctctaag gaagtttttg gccagcttaa 480 ctgataccag tgaaaaagag aaaagaataa ttcaagaatt gacaatattc aaaagaatta 540 atcactcatc agatcaaggg atttcctctt acacaaaatt aaaaggatgt aaagttttgg 600 atcataccgc caagcttcca acagatctac ggctatcagt ttcagtaata gatagtagtg 660 atgaagccac cattcgtttg gcaaacatgt tgaaaattga aaaattgaag actacaagct 720 gtttaaagtt tgttttaaaa gatattggaa atgcatttta tacacaggaa gaggtaacac 780 aacttatgct ttggatcctt gagaatctat cctctcttaa aaatgagaat tcaaatgtgc 840 ttgattggtt aatgccacta aaattcattc atatgtccca gggacatgtg gtagcagctg 900 gtgatctctt tgatcctgat atagaagtac taagggatct cttttataat gaagaagaag 960 cttgtttccc acctacaatt tttacctcac cagatatcct tcactctttg agacagattg 1020 gcttaaaaaa tgaatccagt ctaaaagaaa aagatgttgt acaagtggca agaaaaattg 1080 aagctttaca ggtcagttcc tgtcagaatc aggatgttct catgaagaaa gccaaaacac 1140 tcttactggt cttgaataaa aaccagacac tcttgcagtc ttctgaaggg aagatggcat 1200 tgaagaaaat caaatgggtt ccagcctgca aggaaagacc tccaaattat cccggttcct 1260 tagtctggaa aggggatctc tgtaatcttt gtgcacctcc agatatgtgt gatgcggcac 1320 atgcagttct agtaggctcc tcacttcctc ttgttgaaag tgtccatgtg aacctggagc 1380 aggcgctcag catcttcaca aagcctacta tcaatgctgt cttaaaacac tttaaaactg 1440 ttgttgactg gtatacttca aaaaccttta gtgatgaaga ttactatcag ttccaacata 1500 ttttgcttga aatttatggg ttcatgcatg atcatctgag tgaagggaag gattctttta 1560 aagccttgaa gtttccatgg gtttggactg gcaaaaactt ttgtcctctt gcccaggctg 1620 tgataaagcc aacccatgat ctggatcttc agccttattt atataatgtg cctaaaacca 1680 tggcaaaatt ccaccagctg ttcaaggctt gtggctcaat agaagagttg acatcagatc 1740 atatttccat ggtcattcag aaagtttatc tcaaaagtga ccaggagttg agtgaagaag 1800 aaagtaaaca aaatcttcat ctcatgttga atattatgag atggctctat agcaatcaga 1860 ttccagcaag ccctaataca ccagttccta tttatcacag cagaaatcct tccaaacttg 1920 tcatgaagcc aattcatgaa tgctgttatt gtgacatcaa agttgatgac ctcaatgact 1980 tgcttgaaga ttcagtggaa ccaattatct tggtacatga agatataccc atgaaaactg 2040 cagaatggct aaaagttccg tgccttagta caagactgat caatcctgaa aacatggggt 2100 ttgagcagtc agggcaaaga gagcctctta ctgtaaggat taaaaatatt ttggaagaat 2160 acccttccgt gtcagatatt tttaaagagc tacttcaaaa tgctgatgat gcaaatgcca 2220 cagaatgcag cttcatgatt gatatgagaa ggaatatgga catacgggaa aatctcctgg 2280 acccagggat ggcagcttgt catggacctg ctctgtggtc attcaacaat tctgaattct 2340 cagattcaga tttcttaaac ataacgaggt taggagagtc tttaaaaagg ggagaagttg 2400 acaaggttgg gaaatttggt cttggtttta attctgtgta ccacatcact gacattccca 2460 tcattatgag cagagaattt atgataatgt ttgatccaaa cataaatcat atcagcaaac 2520 acattaaaga tagatcgaat cctggaatca aaattaattg gagtaagcag cagaaaagac 2580 ttaggaagtt ccccaaccag ttcaaaccat ttatagatgt atttggctgt cagttacctt 2640 tggctgttga agctccttac agctacaatg gaactctttt ccgactgtcc tttagaacac 2700 agcaggaagc aaaagtgagt gaagttagca gtacttgcta caatactgcg gatatttact 2760 ccctagtgga tgaatttagt ctttgtgggc acagacttat catttttact cagagtgtaa 2820 actcgatgta tttgaaatac ttgaaaattg aagaaaccaa tcctagctta gcacaagata 2880 caatcataat taagaaaaaa gtttgcccct ccaaagcatt gaatgcacca gttttaagtg 2940 ttttaaaaga agctgctaaa ctcatgaaga cttgtagcag cagcaacaag aagcttccca 3000 cggatgtgcc aaagtcatct tgcattcttc agatcacagt cgaagaattc caccatgtgt 3060 ttaggaggat tgctgactta cagtcaccac tatttcgagg tccagatgat gacccagcta 3120 ctctctttga aatggctaaa tctggccaat caaaaaagcc atcagatgag ttgccacaaa 3180 agacagtaga ttgtaccaca tggcttatat gcacatgcat ggatacagga gaagctctca 3240 agttttcctt gaatgaaagt ggaagaagat tagggctggt tccttgtggg gcagtagggg 3300 ttctcttgca tgaaacccag gaacagaagt ggaccgtgaa accacacata ggagaagtgt 3360 tttgctattt acctctacga atcaaaacag ggttgccaat tcacatcaat gggtgctttg 3420 ctgttacttc aaataggaaa gaaatctgga agacagatac aaaaggtcga tggaatacca 3480 cattcatgag gcatgtcatt gtgaaagctt acttacaagc cctcagtgtc ttacgggacc 3540 tagccattgg tggtgagctg actgattata cttactatgc agtgtggcct gatcctgatc 3600 tagttcatga tgacttctct gtgatctgta aaggatttta tgaagacatt gctcatggga 3660 aggggaagga gttgaccaga gtcttctctg atgggtctat gtgggtttcc atgaagaatg 3720 tgaggtttct ggatgactct atacttcaaa ggaaagatgt tggttcagca gccttcaaga 3780 tatttctgaa gtacctcaag aaaacaggat ccaaaaacct ctgtgctgtt gagcttcctt 3840 cttcagtaaa agcaggattt gaagaggctg gctgtaaaca gatactgctg gaaaatacat 3900 tttcagagaa acagttcttt tcagaagtct tctttcctaa tatccaggaa attgaagcag 3960 aacttagaga tcctctgatg aattttgtcc taaatgaaaa acttgatgag ttctcaggaa 4020 ttcttcgtgt taccccttgt gttccttgct ccttggaggg ccatcctttg gttttgcctt 4080 caagattgat ccatcctgaa ggacgagttg caaagttatt tgatactaaa gatggaagat 4140 tcccttatgg ttccacacag gattacctca atcctattat cttgattaag ctcgttcagt 4200 taggcatggc aaaagatgat attttgtggg atgacatgct agagcgtgca gagtctgtag 4260 ctgagattaa taaaagtgac catgctgctg cctgcttaag gagtagtatt ctgctaagcc 4320 ttattgatga gaagctaaaa ataaaggatc ctagagcaaa ggattttgct gcaaaatatc 4380 aaacaattcc cttcctccca tttctaacaa agccagcagg tttttcttta gaatggaaag 4440 ggaacagctt taagcctgaa accatgtttg cagcaactga catttacaca gctgaatatc 4500 aagatatagt ctgtcttttg caaccaattc ttaatgaaaa ttcccattcc tttagaggct 4560 gtggttcagt gtctttggct gttaaggagt ttttgggttt actaaagaag ccaacagttg 4620 atctggtaat aaaccagttg aagcaagttg caaaatcagt tgatgatggc attacattgt 4680 accaggaaaa tatcaccaac gcttgctaca aatacctcca tgaagcagta ttgcagaatg 4740 aaatggccaa ggcaacaatt attgagaagc taaagccatt ttgtttcatt ctagttgaga 4800 atgtatatgt tgagtcagaa aaggtttctt ttcacttgaa ctttgaagca gcaccatacc 4860 tttatcagtt acctaacaag tataaaaata atttccgtga gctttttgaa agtgtgggtg 4920 tgcgacagtc atttactgtt gaagactttg ccctagtttt ggagtctatt gatcaagaga 4980 gaggaaaaaa acaaataaca gaagagaatt ttcagctttg ccgacgaata atcagtgaag 5040 gcatctggag tctcattaga gaaaagagac aagaattttg tgagaaaaat tatggcaaaa 5100 tattactgcc agacactaac ctgctgctgc tccctgctaa gtcattatgc tacaatgact 5160 gtccctggat aaaagtaaag gactccactg tcaagtattg ccatgccgac ataccccggg 5220 aagtagctgt aaaacttggt gcaataccaa agagacataa agcattagaa agatatgcat 5280 ccaacatctg tttcacagct ctaggtacag aatttgggca gaaagaaaaa ctgaccagca 5340 gaattaagag cattctcaat gcctatcctt cagaaaagga aatgctgaaa gagcttcttc 5400 aaaatgctga tgatgcaaag gccacagaga tctgctttgt gtttgatcct agacagcatc 5460 ctgttgaccg aatatttgat gataagtggg ccccactgca agggccagca ctgtgtgttt 5520 acaacaacca gccatttaca gaagatgatg ttagaggaat tcagaatctt gggaaaggca 5580 ccaaagaagg gaatccttgc aaaacaggac attatggaat cggattcaat tccgtttatc 5640 atattacaga ctgcccttct tttatttctg gcaatgacat cctgggtatt tttgatcccc 5700 atgccagata tgcaccagga gccacatcag ttagccctgg acgcatgttt agagatttgg 5760 atgcagactt tagaacccag ttctcagatg ttctagatct gtacttggga aaccacttta 5820 aactggacaa ttgtacaatg tttagatttc ctctgcgtaa tgcagagatg gcacaagttt 5880 cagaaatttc ttccgttcca tcatcagaca gaatggtcca gaatcttttg gacaagttac 5940 ggtctgatgg ggcagaactt ctaatgtttc tcaaccacat ggagaaaata tctatttgtg 6000 aaatagataa ggccacagga ggtctgaatg tgctctattc agtaaaaggc aagatcactg 6060 atggagaccg attgaaaagg aagcaattcc acgcctctgt aattgacagt gttactaaaa 6120 agagacagct caaggacata ccagttcaac aaataaccta cactatggat actgaggatt 6180 ctgaaggaaa tctgaccaca tggctcatct gtaatagatc aggattttca agtatggaaa 6240 aagtatccaa gagtgtaata tcagctcaca agaaccaaga tatcaccctt ttcccacgtg 6300 gtggagtagc agcctgcatt actcacaatt ataaaaagcc ccacagagcc ttctgctttc 6360 tgcctctctc tttggagaca gggctgccat ttcatgtgaa tggccacttt gctctagatt 6420 cagccagaag aaacttgtgg cgtgatgata atggggttgg tgttcgaagt gactggaata 6480 atagtttaat gacagcatta atagcacctg catatgttga gttactaatc cagttaaaaa 6540 aacggtattt ccctggttct gacccaacat tatcagtttt acagaacaca cccattcatg 6600 tcgtaaagga cacattaaag aagtttctgt ccttctttcc agttaacagg ctggatctgc 6660 agccggactt atattgctta gtaaaagcac tttacagttg cattcatgaa gacatgaagc 6720 gtcttttgcc tgttgttcgg gctccaaata ttgatggctc agatttgcac tctgcagtca 6780 taattacttg gatcaatatg tctacttcaa ataaaactag accatttttt gataacttac 6840 tacaggatga attacagcac cttaaaaatg cagattataa catcacaact cgaaaaacag 6900 tcgcagagaa tgtctacaga ctgaagcacc tgctcttaga aattggtttc aacttggttt 6960 ataactgtga tgaaactgct aacctttacc attgccttgt agatgcagat atccctgtca 7020 gctatgtgac tcctgctgat gttaggtcct tcttaatgac tttctcttct cctgacacta 7080 attgccatat tgggaagctg ccttgtcgtc ttcagcagac taacctaaaa ctttttcaca 7140 gtttaaaact tttagttgat tactgtttta aagatgctga agaaagtgag tttgaagttg 7200 agggactgcc cctactcatt acactggaca gtgtcttgca gatttttgat ggtaaacgac 7260 ccaagtttct aacaacatac catgaattaa ttccatcgcg taaagacttg tttatgaaca 7320 ccttatactt gaaatacagt agtgttttgt tgaactgcaa agttgcaaaa gtgtttgaca 7380 tttccagctt tgctgactta ctctcttctg tgttgcctcg tgagtacaag accaaaaact 7440 gtgcaaagtg gaaagacaat tttgccagtg aatcttggct taagaacgca tggcatttta 7500 tcagtgaatc agtaagtgta acggatgatc aggaagaacc aaagccagca tttgatgtca 7560 ttgttgacat ccttaaagac tgggcattgc ttccaggaac aaagttcact gtgtcaacca 7620 gtcagcttgt ggttcctgag ggagacgtgt tgattcccct gagcctcatg cacattgctg 7680 tgttcccaaa tgctcagagt gataaggttt ttcacgctct gatgaaagct ggctgtattc 7740 agctggcttt gaacaaaatc tgctctaaag acagcgcatt agttcctctg ttgtcatgcc 7800 acacagcaaa catagatagc cctgcaagca tcttgaaggc tgtgcattat atggttcaga 7860 cgtcaacatt tagaactgaa aaactaatgg aaaatgactt tgaagcactt ttgatgtatt 7920 tcaactgtaa tttgagtcac ttgatgtccc aagatgacat aaaaatttta aagtccctcc 7980 catgctacaa atccatcagt ggccgctata tgagcattgc aaaatttgga acgtgctatg 8040 tgcttaccaa aagtattcct tcagctgaag tggaaaaatg gacacagtca tcctcttccg 8100 cgtttcttga agaaaaggtg catttaaaag aactctatga ggtgcttggc tgtgtgccag 8160 tagatgatct ggaggtgtat ttgaaacatc ttctgccaaa aattgaaaat ctctcttatg 8220 atgcaaagtt ggagcacctg atttatctga agaatagact ggcaagcatc gaggaaccgt 8280 cagagattaa ggagcaactt tttgaaaaac tggaaagctt attgattatc cacgatgcca 8340 acaatcgact aaagcaagca aaacatttct atgacagaac tgtgagagtt tttgaagtta 8400 tgcttcctga aaaattgttt attcctaagg agttctttaa aaaattggaa caagtaatca 8460 aacctaaaaa tcaagctgca tttatgacgt cctgggtgga attcttgaga aatattggac 8520 tgaagtacgc gctctcccag cagcagttgt tacagtttgc caaggaaatc agtgtgaggg 8580 caaatacaga aaactggtct aaagaaaccc tgcaaagtac agttgacatc cttctccatc 8640 acatattcca agaacgaatg gatttgttat ctggaaattt tctgaaagaa ctgtccttaa 8700 taccattctt gtgtcctgaa cgggcccccg ctgagtacat tcggtttcac cctcagtacc 8760 aggaggtaaa cggaacactt cctcttataa agttcaatgg agcacaagtg aatccaaagt 8820 tcaagcaatg tgatgtactc cagctgctgt ggacatcttg ccctattctt ccagagaaag 8880 ccacaccgtt gagcattaaa gaacaagaag gcagtgacct cgctccacag gaacagcttg 8940 aacaagtttt aaatatgctt aatgttaacc tggacccccc tcttgataag gtcattaata 9000 attgcagaaa catatgcaac ataacaactt tggatgagga aatggtaaaa actagagcaa 9060 aggtcctaag gagcatatat gaatttctga gtgcagaaaa acgagagttc cgttttcagc 9120 ttcggggtgt ggcctttgta atggtagaag acggatggaa acttctgaag cctgaggaag 9180 tagtgataaa cctggagtat gaggctgatt ttaaacctta tctgtacaag ctgcctttag 9240 agcttggcac ttttcatcag ctgttcaaac atttaggtac tgaagatatc atttccacta 9300 agcaatatgt tgaagtgtta agccgaatat tcaaaagctc tgaaggaaag cagctagacc 9360 ctaatgaaat gcgtacagtt aagagagtgg tttctggcct attcaagagt ctacaaaatg 9420 attcagtcaa ggtgaggagt gacctggaga atgcccggga cctcgcactc taccttccaa 9480 gccaggatgg gaagttggtg aagtcaagca tcttggtgtt cgatgatgcg ccacattata 9540 aaagtaggat ccaggggaat attggcgtgc agatgctagt tgatcttagc cagtgctact 9600 tagggaaaga ccatggattt cacactaagc tgataatgct ctttcctcaa aagcttcgac 9660 ctcgtctgct gagcagtata cttgaagagc agcttgatga ggagacccct aaagtgtgcc 9720 agtttggcgc attgtgctct cttcagggaa gactgcagct tctcttgtct tcagagcagt 9780 tcatcacagg actcattcga atcatgaagc atgaaaatga taatgctttc ctggccaatg 9840 aagaaaaagc cataagactt tgcaaagctc taagagaagg gctgaaagtt tcctgttttg 9900 agaagcttca gacaacatta agggttaaag gttttaatcc tattccccat agcaggagtg 9960 aaactttcgc ttttctaaag cgatttggca atgcagtcat cttgctctac atccaacatt 10020 cagacagcaa agacattaac tttctgctag ccttagcgat gacacttaaa tcagcaactg 10080 acaatttgat ttctgacacg tcatacttaa ttgctatgct gggatgcaat gacatttaca 10140 ggatcagtga gaagcttgac agtttagggg tgaaatacga ctcctctgag ccatcaaaac 10200 tggaactccc catgcctggc acaccaatac ccgctgagat ccattacaca ctacttatgg 10260 atccaatgaa tgttttttat cctggggaat atgttggtta ccttgtggat gctgaaggtg 10320 gtgatatcta tgggtcatac cagccaacat acacatacgc aattattgtg caagaagttg 10380 aaagagaaga tgctgacaat actagtttct taggaaagat ctatcagatc gatattggct 10440 acagtgaata taagatagtc agctctcttg atctgtacaa gttctcaagg cctgatgaaa 10500 gctcccaaaa cagagacagt gctcccacca caccaacaag ccccaccgaa ttcctgactc 10560 ctggtctgag aagcatccct cctcttttct ctggcaagga gagccacaag tctccctcca 10620 ccaaacacca ttcccccaga aagctcaagg tgaatgcttt accagaaatc ttaaaagaag 10680 tgacatcagt ggtggagcaa gcttggaagc ttccagaatc agagcggaaa aagatcatta 10740 gacgcttgta tttgaagtgg caccctgaca aaaatccaga aaatcatgat attgctaatg 10800 aagtgttcaa gcacctgcag aatgaaatca acagattaga aaaacaggct tttctggatc 10860 aaaatgcaga cagagcttca agaagaacat tttcaacctc tgcatctcga tttcagtcag 10920 acaagtactc atttcaaaga ttttacactt cgtggaatca agaagccaca agtcataaat 10980 ctgaaaggca acagcaaagc aaagagaaat gccctccttc tgctggacag acatactctc 11040 aaaggttctt tgttcctccc accttcaagt cagtgggcaa tccagtggaa gcccggagat 11100 ggttaagaca agccagagca aacttctcag ctgccaggaa tgaccttcac aaaaatgcca 11160 atgaatgggt gtgcttcaag tgttaccttt ccaccaagct ggctttgatt gcagccgact 11220 atgctgtcag ggggaaatct gataaagatg taaagccaac tgcacttgca caaaagatag 11280 aggagtacag tcagcagctg gaaggactga caaacgatgt gcacacattg gaagcttatg 11340 gtgtagacag cttgaaaaca aggtaccctg atttgcttcc ttttccgcag attcccaatg 11400 acaggttcac atctgaggtt gccatgaggg tgatggaatg cactgcctgt atcatcataa 11460 aacttgaaaa ttttatacaa cagaaggtgt ga 11492 <210> SEQ ID NO 4 <211> LENGTH: 3830 <212> TYPE: PRT <213> ORGANISM: Mus musculus <400> SEQUENCE: 4 Met Asn Thr Phe Trp Pro Gly Arg Glu Leu Val Val Gln Trp Tyr Pro 1 5 10 15 Phe Ser Glu Asp Lys Arg His Pro Ser Leu Ser Trp Leu Lys Met Val 20 25 30 Trp Lys Asn Leu Tyr Ile His Phe Ser Glu Asp Leu Thr Leu Phe Asp 35 40 45 Glu Met Pro Leu Ile Pro Arg Thr Leu Leu Asn Glu Asp Gln Thr Cys 50 55 60 Val Glu Leu Ile Arg Leu Arg Ile Pro Ser Val Val Ile Leu Asp Asp 65 70 75 80 Glu Thr Glu Ala Gln Leu Pro Glu Phe Leu Ala Asp Ile Val Gln Lys 85 90 95 Leu Gly Gly Ile Val Leu Lys Arg Leu Asp Thr Ser Ile Gln His Pro 100 105 110 Leu Val Lys Lys Tyr Ile His Ser Pro Leu Pro Ser Ala Ile Leu Gln 115 120 125 Ile Met Glu Lys Ile Pro Leu Gln Lys Leu Cys Asn Gln Ile Ala Ser 130 135 140 Leu Leu Pro Thr His Lys Asp Ala Leu Arg Lys Phe Leu Ala Ser Leu 145 150 155 160 Thr Asp Thr Ser Glu Lys Glu Lys Arg Ile Ile Gln Glu Leu Thr Ile 165 170 175 Phe Lys Arg Ile Asn His Ser Ser Asp Gln Gly Ile Ser Ser Tyr Thr 180 185 190 Lys Leu Lys Gly Cys Lys Val Leu Asp His Thr Ala Lys Leu Pro Thr 195 200 205 Asp Leu Arg Leu Ser Val Ser Val Ile Asp Ser Ser Asp Glu Ala Thr 210 215 220 Ile Arg Leu Ala Asn Met Leu Lys Ile Glu Lys Leu Lys Thr Thr Ser 225 230 235 240 Cys Leu Lys Phe Val Leu Lys Asp Ile Gly Asn Ala Phe Tyr Thr Gln 245 250 255 Glu Glu Val Thr Gln Leu Met Leu Trp Ile Leu Glu Asn Leu Ser Ser 260 265 270 Leu Lys Asn Glu Asn Ser Asn Val Leu Asp Trp Leu Met Pro Leu Lys 275 280 285 Phe Ile His Met Ser Gln Gly His Val Val Ala Ala Gly Asp Leu Phe 290 295 300 Asp Pro Asp Ile Glu Val Leu Arg Asp Leu Phe Tyr Asn Glu Glu Glu 305 310 315 320 Ala Cys Phe Pro Pro Thr Ile Phe Thr Ser Pro Asp Ile Leu His Ser 325 330 335 Leu Arg Gln Ile Gly Leu Lys Asn Glu Ser Ser Leu Lys Glu Lys Asp 340 345 350 Val Val Gln Val Ala Arg Lys Ile Glu Ala Leu Gln Val Ser Ser Cys 355 360 365 Gln Asn Gln Asp Val Leu Met Lys Lys Ala Lys Thr Leu Leu Leu Val 370 375 380 Leu Asn Lys Asn Gln Thr Leu Leu Gln Ser Ser Glu Gly Lys Met Ala 385 390 395 400 Leu Lys Lys Ile Lys Trp Val Pro Ala Cys Lys Glu Arg Pro Pro Asn 405 410 415 Tyr Pro Gly Ser Leu Val Trp Lys Gly Asp Leu Cys Asn Leu Cys Ala 420 425 430 Pro Pro Asp Met Cys Asp Ala Ala His Ala Val Leu Val Gly Ser Ser 435 440 445 Leu Pro Leu Val Glu Ser Val His Val Asn Leu Glu Gln Ala Leu Ser 450 455 460 Ile Phe Thr Lys Pro Thr Ile Asn Ala Val Leu Lys His Phe Lys Thr 465 470 475 480 Val Val Asp Trp Tyr Thr Ser Lys Thr Phe Ser Asp Glu Asp Tyr Tyr 485 490 495 Gln Phe Gln His Ile Leu Leu Glu Ile Tyr Gly Phe Met His Asp His 500 505 510 Leu Ser Glu Gly Lys Asp Ser Phe Lys Ala Leu Lys Phe Pro Trp Val 515 520 525 Trp Thr Gly Lys Asn Phe Cys Pro Leu Ala Gln Ala Val Ile Lys Pro 530 535 540 Thr His Asp Leu Asp Leu Gln Pro Tyr Leu Tyr Asn Val Pro Lys Thr 545 550 555 560 Met Ala Lys Phe His Gln Leu Phe Lys Ala Cys Gly Ser Ile Glu Glu 565 570 575 Leu Thr Ser Asp His Ile Ser Met Val Ile Gln Lys Val Tyr Leu Lys 580 585 590 Ser Asp Gln Glu Leu Ser Glu Glu Glu Ser Lys Gln Asn Leu His Leu 595 600 605 Met Leu Asn Ile Met Arg Trp Leu Tyr Ser Asn Gln Ile Pro Ala Ser 610 615 620 Pro Asn Thr Pro Val Pro Ile Tyr His Ser Arg Asn Pro Ser Lys Leu 625 630 635 640 Val Met Lys Pro Ile His Glu Cys Cys Tyr Cys Asp Ile Lys Val Asp 645 650 655 Asp Leu Asn Asp Leu Leu Glu Asp Ser Val Glu Pro Ile Ile Leu Val 660 665 670 His Glu Asp Ile Pro Met Lys Thr Ala Glu Trp Leu Lys Val Pro Cys 675 680 685 Leu Ser Thr Arg Leu Ile Asn Pro Glu Asn Met Gly Phe Glu Gln Ser 690 695 700 Gly Gln Arg Glu Pro Leu Thr Val Arg Ile Lys Asn Ile Leu Glu Glu 705 710 715 720 Tyr Pro Ser Val Ser Asp Ile Phe Lys Glu Leu Leu Gln Asn Ala Asp 725 730 735 Asp Ala Asn Ala Thr Glu Cys Ser Phe Met Ile Asp Met Arg Arg Asn 740 745 750 Met Asp Ile Arg Glu Asn Leu Leu Asp Pro Gly Met Ala Ala Cys His 755 760 765 Gly Pro Ala Leu Trp Ser Phe Asn Asn Ser Glu Phe Ser Asp Ser Asp 770 775 780 Phe Leu Asn Ile Thr Arg Leu Gly Glu Ser Leu Lys Arg Gly Glu Val 785 790 795 800 Asp Lys Val Gly Lys Phe Gly Leu Gly Phe Asn Ser Val Tyr His Ile 805 810 815 Thr Asp Ile Pro Ile Ile Met Ser Arg Glu Phe Met Ile Met Phe Asp 820 825 830 Pro Asn Ile Asn His Ile Ser Lys His Ile Lys Asp Arg Ser Asn Pro 835 840 845 Gly Ile Lys Ile Asn Trp Ser Lys Gln Gln Lys Arg Leu Arg Lys Phe 850 855 860 Pro Asn Gln Phe Lys Pro Phe Ile Asp Val Phe Gly Cys Gln Leu Pro 865 870 875 880 Leu Ala Val Glu Ala Pro Tyr Ser Tyr Asn Gly Thr Leu Phe Arg Leu 885 890 895 Ser Phe Arg Thr Gln Gln Glu Ala Lys Val Ser Glu Val Ser Ser Thr 900 905 910 Cys Tyr Asn Thr Ala Asp Ile Tyr Ser Leu Val Asp Glu Phe Ser Leu 915 920 925 Cys Gly His Arg Leu Ile Ile Phe Thr Gln Ser Val Asn Ser Met Tyr 930 935 940 Leu Lys Tyr Leu Lys Ile Glu Glu Thr Asn Pro Ser Leu Ala Gln Asp 945 950 955 960 Thr Ile Ile Ile Lys Lys Lys Val Cys Pro Ser Lys Ala Leu Asn Ala 965 970 975 Pro Val Leu Ser Val Leu Lys Glu Ala Ala Lys Leu Met Lys Thr Cys 980 985 990 Ser Ser Ser Asn Lys Lys Leu Pro Thr Asp Val Pro Lys Ser Ser Cys 995 1000 1005 Ile Leu Gln Ile Thr Val Glu Glu Phe His His Val Phe Arg Arg Ile 1010 1015 1020 Ala Asp Leu Gln Ser Pro Leu Phe Arg Gly Pro Asp Asp Asp Pro Ala 1025 1030 1035 1040 Thr Leu Phe Glu Met Ala Lys Ser Gly Gln Ser Lys Lys Pro Ser Asp 1045 1050 1055 Glu Leu Pro Gln Lys Thr Val Asp Cys Thr Thr Trp Leu Ile Cys Thr 1060 1065 1070 Cys Met Asp Thr Gly Glu Ala Leu Lys Phe Ser Leu Asn Glu Ser Gly 1075 1080 1085 Arg Arg Leu Gly Leu Val Pro Cys Gly Ala Val Gly Val Leu Leu His 1090 1095 1100 Glu Thr Gln Glu Gln Lys Trp Thr Val Lys Pro His Ile Gly Glu Val 1105 1110 1115 1120 Phe Cys Tyr Leu Pro Leu Arg Ile Lys Thr Gly Leu Pro Ile His Ile 1125 1130 1135 Asn Gly Cys Phe Ala Val Thr Ser Asn Arg Lys Glu Ile Trp Lys Thr 1140 1145 1150 Asp Thr Lys Gly Arg Trp Asn Thr Thr Phe Met Arg His Val Ile Val 1155 1160 1165 Lys Ala Tyr Leu Gln Ala Leu Ser Val Leu Arg Asp Leu Ala Ile Gly 1170 1175 1180 Gly Glu Leu Thr Asp Tyr Thr Tyr Tyr Ala Val Trp Pro Asp Pro Asp 1185 1190 1195 1200 Leu Val His Asp Asp Phe Ser Val Ile Cys Lys Gly Phe Tyr Glu Asp 1205 1210 1215 Ile Ala His Gly Lys Gly Lys Glu Leu Thr Arg Val Phe Ser Asp Gly 1220 1225 1230 Ser Met Trp Val Ser Met Lys Asn Val Arg Phe Leu Asp Asp Ser Ile 1235 1240 1245 Leu Gln Arg Lys Asp Val Gly Ser Ala Ala Phe Lys Ile Phe Leu Lys 1250 1255 1260 Tyr Leu Lys Lys Thr Gly Ser Lys Asn Leu Cys Ala Val Glu Leu Pro 1265 1270 1275 1280 Ser Ser Val Lys Ala Gly Phe Glu Glu Ala Gly Cys Lys Gln Ile Leu 1285 1290 1295 Leu Glu Asn Thr Phe Ser Glu Lys Gln Phe Phe Ser Glu Val Phe Phe 1300 1305 1310 Pro Asn Ile Gln Glu Ile Glu Ala Glu Leu Arg Asp Pro Leu Met Asn 1315 1320 1325 Phe Val Leu Asn Glu Lys Leu Asp Glu Phe Ser Gly Ile Leu Arg Val 1330 1335 1340 Thr Pro Cys Val Pro Cys Ser Leu Glu Gly His Pro Leu Val Leu Pro 1345 1350 1355 1360 Ser Arg Leu Ile His Pro Glu Gly Arg Val Ala Lys Leu Phe Asp Thr 1365 1370 1375 Lys Asp Gly Arg Phe Pro Tyr Gly Ser Thr Gln Asp Tyr Leu Asn Pro 1380 1385 1390 Ile Ile Leu Ile Lys Leu Val Gln Leu Gly Met Ala Lys Asp Asp Ile 1395 1400 1405 Leu Trp Asp Asp Met Leu Glu Arg Ala Glu Ser Val Ala Glu Ile Asn 1410 1415 1420 Lys Ser Asp His Ala Ala Ala Cys Leu Arg Ser Ser Ile Leu Leu Ser 1425 1430 1435 1440 Leu Ile Asp Glu Lys Leu Lys Ile Lys Asp Pro Arg Ala Lys Asp Phe 1445 1450 1455 Ala Ala Lys Tyr Gln Thr Ile Pro Phe Leu Pro Phe Leu Thr Lys Pro 1460 1465 1470 Ala Gly Phe Ser Leu Glu Trp Lys Gly Asn Ser Phe Lys Pro Glu Thr 1475 1480 1485 Met Phe Ala Ala Thr Asp Ile Tyr Thr Ala Glu Tyr Gln Asp Ile Val 1490 1495 1500 Cys Leu Leu Gln Pro Ile Leu Asn Glu Asn Ser His Ser Phe Arg Gly 1505 1510 1515 1520 Cys Gly Ser Val Ser Leu Ala Val Lys Glu Phe Leu Gly Leu Leu Lys 1525 1530 1535 Lys Pro Thr Val Asp Leu Val Ile Asn Gln Leu Lys Gln Val Ala Lys 1540 1545 1550 Ser Val Asp Asp Gly Ile Thr Leu Tyr Gln Glu Asn Ile Thr Asn Ala 1555 1560 1565 Cys Tyr Lys Tyr Leu His Glu Ala Val Leu Gln Asn Glu Met Ala Lys 1570 1575 1580 Ala Thr Ile Ile Glu Lys Leu Lys Pro Phe Cys Phe Ile Leu Val Glu 1585 1590 1595 1600 Asn Val Tyr Val Glu Ser Glu Lys Val Ser Phe His Leu Asn Phe Glu 1605 1610 1615 Ala Ala Pro Tyr Leu Tyr Gln Leu Pro Asn Lys Tyr Lys Asn Asn Phe 1620 1625 1630 Arg Glu Leu Phe Glu Ser Val Gly Val Arg Gln Ser Phe Thr Val Glu 1635 1640 1645 Asp Phe Ala Leu Val Leu Glu Ser Ile Asp Gln Glu Arg Gly Lys Lys 1650 1655 1660 Gln Ile Thr Glu Glu Asn Phe Gln Leu Cys Arg Arg Ile Ile Ser Glu 1665 1670 1675 1680 Gly Ile Trp Ser Leu Ile Arg Glu Lys Arg Gln Glu Phe Cys Glu Lys 1685 1690 1695 Asn Tyr Gly Lys Ile Leu Leu Pro Asp Thr Asn Leu Leu Leu Leu Pro 1700 1705 1710 Ala Lys Ser Leu Cys Tyr Asn Asp Cys Pro Trp Ile Lys Val Lys Asp 1715 1720 1725 Ser Thr Val Lys Tyr Cys His Ala Asp Ile Pro Arg Glu Val Ala Val 1730 1735 1740 Lys Leu Gly Ala Ile Pro Lys Arg His Lys Ala Leu Glu Arg Tyr Ala 1745 1750 1755 1760 Ser Asn Ile Cys Phe Thr Ala Leu Gly Thr Glu Phe Gly Gln Lys Glu 1765 1770 1775 Lys Leu Thr Ser Arg Ile Lys Ser Ile Leu Asn Ala Tyr Pro Ser Glu 1780 1785 1790 Lys Glu Met Leu Lys Glu Leu Leu Gln Asn Ala Asp Asp Ala Lys Ala 1795 1800 1805 Thr Glu Ile Cys Phe Val Phe Asp Pro Arg Gln His Pro Val Asp Arg 1810 1815 1820 Ile Phe Asp Asp Lys Trp Ala Pro Leu Gln Gly Pro Ala Leu Cys Val 1825 1830 1835 1840 Tyr Asn Asn Gln Pro Phe Thr Glu Asp Asp Val Arg Gly Ile Gln Asn 1845 1850 1855 Leu Gly Lys Gly Thr Lys Glu Gly Asn Pro Cys Lys Thr Gly His Tyr 1860 1865 1870 Gly Ile Gly Phe Asn Ser Val Tyr His Ile Thr Asp Cys Pro Ser Phe 1875 1880 1885 Ile Ser Gly Asn Asp Ile Leu Gly Ile Phe Asp Pro His Ala Arg Tyr 1890 1895 1900 Ala Pro Gly Ala Thr Ser Val Ser Pro Gly Arg Met Phe Arg Asp Leu 1905 1910 1915 1920 Asp Ala Asp Phe Arg Thr Gln Phe Ser Asp Val Leu Asp Leu Tyr Leu 1925 1930 1935 Gly Asn His Phe Lys Leu Asp Asn Cys Thr Met Phe Arg Phe Pro Leu 1940 1945 1950 Arg Asn Ala Glu Met Ala Gln Val Ser Glu Ile Ser Ser Val Pro Ser 1955 1960 1965 Ser Asp Arg Met Val Gln Asn Leu Leu Asp Lys Leu Arg Ser Asp Gly 1970 1975 1980 Ala Glu Leu Leu Met Phe Leu Asn His Met Glu Lys Ile Ser Ile Cys 1985 1990 1995 2000 Glu Ile Asp Lys Ala Thr Gly Gly Leu Asn Val Leu Tyr Ser Val Lys 2005 2010 2015 Gly Lys Ile Thr Asp Gly Asp Arg Leu Lys Arg Lys Gln Phe His Ala 2020 2025 2030 Ser Val Ile Asp Ser Val Thr Lys Lys Arg Gln Leu Lys Asp Ile Pro 2035 2040 2045 Val Gln Gln Ile Thr Tyr Thr Met Asp Thr Glu Asp Ser Glu Gly Asn 2050 2055 2060 Leu Thr Thr Trp Leu Ile Cys Asn Arg Ser Gly Phe Ser Ser Met Glu 2065 2070 2075 2080 Lys Val Ser Lys Ser Val Ile Ser Ala His Lys Asn Gln Asp Ile Thr 2085 2090 2095 Leu Phe Pro Arg Gly Gly Val Ala Ala Cys Ile Thr His Asn Tyr Lys 2100 2105 2110 Lys Pro His Arg Ala Phe Cys Phe Leu Pro Leu Ser Leu Glu Thr Gly 2115 2120 2125 Leu Pro Phe His Val Asn Gly His Phe Ala Leu Asp Ser Ala Arg Arg 2130 2135 2140 Asn Leu Trp Arg Asp Asp Asn Gly Val Gly Val Arg Ser Asp Trp Asn 2145 2150 2155 2160 Asn Ser Leu Met Thr Ala Leu Ile Ala Pro Ala Tyr Val Glu Leu Leu 2165 2170 2175 Ile Gln Leu Lys Lys Arg Tyr Phe Pro Gly Ser Asp Pro Thr Leu Ser 2180 2185 2190 Val Leu Gln Asn Thr Pro Ile His Val Val Lys Asp Thr Leu Lys Lys 2195 2200 2205 Phe Leu Ser Phe Phe Pro Val Asn Arg Leu Asp Leu Gln Pro Asp Leu 2210 2215 2220 Tyr Cys Leu Val Lys Ala Leu Tyr Ser Cys Ile His Glu Asp Met Lys 2225 2230 2235 2240 Arg Leu Leu Pro Val Val Arg Ala Pro Asn Ile Asp Gly Ser Asp Leu 2245 2250 2255 His Ser Ala Val Ile Ile Thr Trp Ile Asn Met Ser Thr Ser Asn Lys 2260 2265 2270 Thr Arg Pro Phe Phe Asp Asn Leu Leu Gln Asp Glu Leu Gln His Leu 2275 2280 2285 Lys Asn Ala Asp Tyr Asn Ile Thr Thr Arg Lys Thr Val Ala Glu Asn 2290 2295 2300 Val Tyr Arg Leu Lys His Leu Leu Leu Glu Ile Gly Phe Asn Leu Val 2305 2310 2315 2320 Tyr Asn Cys Asp Glu Thr Ala Asn Leu Tyr His Cys Leu Val Asp Ala 2325 2330 2335 Asp Ile Pro Val Ser Tyr Val Thr Pro Ala Asp Val Arg Ser Phe Leu 2340 2345 2350 Met Thr Phe Ser Ser Pro Asp Thr Asn Cys His Ile Gly Lys Leu Pro 2355 2360 2365 Cys Arg Leu Gln Gln Thr Asn Leu Lys Leu Phe His Ser Leu Lys Leu 2370 2375 2380 Leu Val Asp Tyr Cys Phe Lys Asp Ala Glu Glu Ser Glu Phe Glu Val 2385 2390 2395 2400 Glu Gly Leu Pro Leu Leu Ile Thr Leu Asp Ser Val Leu Gln Ile Phe 2405 2410 2415 Asp Gly Lys Arg Pro Lys Phe Leu Thr Thr Tyr His Glu Leu Ile Pro 2420 2425 2430 Ser Arg Lys Asp Leu Phe Met Asn Thr Leu Tyr Leu Lys Tyr Ser Ser 2435 2440 2445 Val Leu Leu Asn Cys Lys Val Ala Lys Val Phe Asp Ile Ser Ser Phe 2450 2455 2460 Ala Asp Leu Leu Ser Ser Val Leu Pro Arg Glu Tyr Lys Thr Lys Asn 2465 2470 2475 2480 Cys Ala Lys Trp Lys Asp Asn Phe Ala Ser Glu Ser Trp Leu Lys Asn 2485 2490 2495 Ala Trp His Phe Ile Ser Glu Ser Val Ser Val Thr Asp Asp Gln Glu 2500 2505 2510 Glu Pro Lys Pro Ala Phe Asp Val Ile Val Asp Ile Leu Lys Asp Trp 2515 2520 2525 Ala Leu Leu Pro Gly Thr Lys Phe Thr Val Ser Thr Ser Gln Leu Val 2530 2535 2540 Val Pro Glu Gly Asp Val Leu Ile Pro Leu Ser Leu Met His Ile Ala 2545 2550 2555 2560 Val Phe Pro Asn Ala Gln Ser Asp Lys Val Phe His Ala Leu Met Lys 2565 2570 2575 Ala Gly Cys Ile Gln Leu Ala Leu Asn Lys Ile Cys Ser Lys Asp Ser 2580 2585 2590 Ala Leu Val Pro Leu Leu Ser Cys His Thr Ala Asn Ile Asp Ser Pro 2595 2600 2605 Ala Ser Ile Leu Lys Ala Val His Tyr Met Val Gln Thr Ser Thr Phe 2610 2615 2620 Arg Thr Glu Lys Leu Met Glu Asn Asp Phe Glu Ala Leu Leu Met Tyr 2625 2630 2635 2640 Phe Asn Cys Asn Leu Ser His Leu Met Ser Gln Asp Asp Ile Lys Ile 2645 2650 2655 Leu Lys Ser Leu Pro Cys Tyr Lys Ser Ile Ser Gly Arg Tyr Met Ser 2660 2665 2670 Ile Ala Lys Phe Gly Thr Cys Tyr Val Leu Thr Lys Ser Ile Pro Ser 2675 2680 2685 Ala Glu Val Glu Lys Trp Thr Gln Ser Ser Ser Ser Ala Phe Leu Glu 2690 2695 2700 Glu Lys Val His Leu Lys Glu Leu Tyr Glu Val Leu Gly Cys Val Pro 2705 2710 2715 2720 Val Asp Asp Leu Glu Val Tyr Leu Lys His Leu Leu Pro Lys Ile Glu 2725 2730 2735 Asn Leu Ser Tyr Asp Ala Lys Leu Glu His Leu Ile Tyr Leu Lys Asn 2740 2745 2750 Arg Leu Ala Ser Ile Glu Glu Pro Ser Glu Ile Lys Glu Gln Leu Phe 2755 2760 2765 Glu Lys Leu Glu Ser Leu Leu Ile Ile His Asp Ala Asn Asn Arg Leu 2770 2775 2780 Lys Gln Ala Lys His Phe Tyr Asp Arg Thr Val Arg Val Phe Glu Val 2785 2790 2795 2800 Met Leu Pro Glu Lys Leu Phe Ile Pro Lys Glu Phe Phe Lys Lys Leu 2805 2810 2815 Glu Gln Val Ile Lys Pro Lys Asn Gln Ala Ala Phe Met Thr Ser Trp 2820 2825 2830 Val Glu Phe Leu Arg Asn Ile Gly Leu Lys Tyr Ala Leu Ser Gln Gln 2835 2840 2845 Gln Leu Leu Gln Phe Ala Lys Glu Ile Ser Val Arg Ala Asn Thr Glu 2850 2855 2860 Asn Trp Ser Lys Glu Thr Leu Gln Ser Thr Val Asp Ile Leu Leu His 2865 2870 2875 2880 His Ile Phe Gln Glu Arg Met Asp Leu Leu Ser Gly Asn Phe Leu Lys 2885 2890 2895 Glu Leu Ser Leu Ile Pro Phe Leu Cys Pro Glu Arg Ala Pro Ala Glu 2900 2905 2910 Tyr Ile Arg Phe His Pro Gln Tyr Gln Glu Val Asn Gly Thr Leu Pro 2915 2920 2925 Leu Ile Lys Phe Asn Gly Ala Gln Val Asn Pro Lys Phe Lys Gln Cys 2930 2935 2940 Asp Val Leu Gln Leu Leu Trp Thr Ser Cys Pro Ile Leu Pro Glu Lys 2945 2950 2955 2960 Ala Thr Pro Leu Ser Ile Lys Glu Gln Glu Gly Ser Asp Leu Ala Pro 2965 2970 2975 Gln Glu Gln Leu Glu Gln Val Leu Asn Met Leu Asn Val Asn Leu Asp 2980 2985 2990 Pro Pro Leu Asp Lys Val Ile Asn Asn Cys Arg Asn Ile Cys Asn Ile 2995 3000 3005 Thr Thr Leu Asp Glu Glu Met Val Lys Thr Arg Ala Lys Val Leu Arg 3010 3015 3020 Ser Ile Tyr Glu Phe Leu Ser Ala Glu Lys Arg Glu Phe Arg Phe Gln 3025 3030 3035 3040 Leu Arg Gly Val Ala Phe Val Met Val Glu Asp Gly Trp Lys Leu Leu 3045 3050 3055 Lys Pro Glu Glu Val Val Ile Asn Leu Glu Tyr Glu Ala Asp Phe Lys 3060 3065 3070 Pro Tyr Leu Tyr Lys Leu Pro Leu Glu Leu Gly Thr Phe His Gln Leu 3075 3080 3085 Phe Lys His Leu Gly Thr Glu Asp Ile Ile Ser Thr Lys Gln Tyr Val 3090 3095 3100 Glu Val Leu Ser Arg Ile Phe Lys Ser Ser Glu Gly Lys Gln Leu Asp 3105 3110 3115 3120 Pro Asn Glu Met Arg Thr Val Lys Arg Val Val Ser Gly Leu Phe Lys 3125 3130 3135 Ser Leu Gln Asn Asp Ser Val Lys Val Arg Ser Asp Leu Glu Asn Ala 3140 3145 3150 Arg Asp Leu Ala Leu Tyr Leu Pro Ser Gln Asp Gly Lys Leu Val Lys 3155 3160 3165 Ser Ser Ile Leu Val Phe Asp Asp Ala Pro His Tyr Lys Ser Arg Ile 3170 3175 3180 Gln Gly Asn Ile Gly Val Gln Met Leu Val Asp Leu Ser Gln Cys Tyr 3185 3190 3195 3200 Leu Gly Lys Asp His Gly Phe His Thr Lys Leu Ile Met Leu Phe Pro 3205 3210 3215 Gln Lys Leu Arg Pro Arg Leu Leu Ser Ser Ile Leu Glu Glu Gln Leu 3220 3225 3230 Asp Glu Glu Thr Pro Lys Val Cys Gln Phe Gly Ala Leu Cys Ser Leu 3235 3240 3245 Gln Gly Arg Leu Gln Leu Leu Leu Ser Ser Glu Gln Phe Ile Thr Gly 3250 3255 3260 Leu Ile Arg Ile Met Lys His Glu Asn Asp Asn Ala Phe Leu Ala Asn 3265 3270 3275 3280 Glu Glu Lys Ala Ile Arg Leu Cys Lys Ala Leu Arg Glu Gly Leu Lys 3285 3290 3295 Val Ser Cys Phe Glu Lys Leu Gln Thr Thr Leu Arg Val Lys Gly Phe 3300 3305 3310 Asn Pro Ile Pro His Ser Arg Ser Glu Thr Phe Ala Phe Leu Lys Arg 3315 3320 3325 Phe Gly Asn Ala Val Ile Leu Leu Tyr Ile Gln His Ser Asp Ser Lys 3330 3335 3340 Asp Ile Asn Phe Leu Leu Ala Leu Ala Met Thr Leu Lys Ser Ala Thr 3345 3350 3355 3360 Asp Asn Leu Ile Ser Asp Thr Ser Tyr Leu Ile Ala Met Leu Gly Cys 3365 3370 3375 Asn Asp Ile Tyr Arg Ile Ser Glu Lys Leu Asp Ser Leu Gly Val Lys 3380 3385 3390 Tyr Asp Ser Ser Glu Pro Ser Lys Leu Glu Leu Pro Met Pro Gly Thr 3395 3400 3405 Pro Ile Pro Ala Glu Ile His Tyr Thr Leu Leu Met Asp Pro Met Asn 3410 3415 3420 Val Phe Tyr Pro Gly Glu Tyr Val Gly Tyr Leu Val Asp Ala Glu Gly 3425 3430 3435 3440 Gly Asp Ile Tyr Gly Ser Tyr Gln Pro Thr Tyr Thr Tyr Ala Ile Ile 3445 3450 3455 Val Gln Glu Val Glu Arg Glu Asp Ala Asp Asn Thr Ser Phe Leu Gly 3460 3465 3470 Lys Ile Tyr Gln Ile Asp Ile Gly Tyr Ser Glu Tyr Lys Ile Val Ser 3475 3480 3485 Ser Leu Asp Leu Tyr Lys Phe Ser Arg Pro Asp Glu Ser Ser Gln Asn 3490 3495 3500 Arg Asp Ser Ala Pro Thr Thr Pro Thr Ser Pro Thr Glu Phe Leu Thr 3505 3510 3515 3520 Pro Gly Leu Arg Ser Ile Pro Pro Leu Phe Ser Gly Lys Glu Ser His 3525 3530 3535 Lys Ser Pro Ser Thr Lys His His Ser Pro Arg Lys Leu Lys Val Asn 3540 3545 3550 Ala Leu Pro Glu Ile Leu Lys Glu Val Thr Ser Val Val Glu Gln Ala 3555 3560 3565 Trp Lys Leu Pro Glu Ser Glu Arg Lys Lys Ile Ile Arg Arg Leu Tyr 3570 3575 3580 Leu Lys Trp His Pro Asp Lys Asn Pro Glu Asn His Asp Ile Ala Asn 3585 3590 3595 3600 Glu Val Phe Lys His Leu Gln Asn Glu Ile Asn Arg Leu Glu Lys Gln 3605 3610 3615 Ala Phe Leu Asp Gln Asn Ala Asp Arg Ala Ser Arg Arg Thr Phe Ser 3620 3625 3630 Thr Ser Ala Ser Arg Phe Gln Ser Asp Lys Tyr Ser Phe Gln Arg Phe 3635 3640 3645 Tyr Thr Ser Trp Asn Gln Glu Ala Thr Ser His Lys Ser Glu Arg Gln 3650 3655 3660 Gln Gln Ser Lys Glu Lys Cys Pro Pro Ser Ala Gly Gln Thr Tyr Ser 3665 3670 3675 3680 Gln Arg Phe Phe Val Pro Pro Thr Phe Lys Ser Val Gly Asn Pro Val 3685 3690 3695 Glu Ala Arg Arg Trp Leu Arg Gln Ala Arg Ala Asn Phe Ser Ala Ala 3700 3705 3710 Arg Asn Asp Leu His Lys Asn Ala Asn Glu Trp Val Cys Phe Lys Cys 3715 3720 3725 Tyr Leu Ser Thr Lys Leu Ala Leu Ile Ala Ala Asp Tyr Ala Val Arg 3730 3735 3740 Gly Lys Ser Asp Lys Asp Val Lys Pro Thr Ala Leu Ala Gln Lys Ile 3745 3750 3755 3760 Glu Glu Tyr Ser Gln Gln Leu Glu Gly Leu Thr Asn Asp Val His Thr 3765 3770 3775 Leu Glu Ala Tyr Gly Val Asp Ser Leu Lys Thr Arg Tyr Pro Asp Leu 3780 3785 3790 Leu Pro Phe Pro Gln Ile Pro Asn Asp Arg Phe Thr Ser Glu Val Ala 3795 3800 3805 Met Arg Val Met Glu Cys Thr Ala Cys Ile Ile Ile Lys Leu Glu Asn 3810 3815 3820 Phe Ile Gln Gln Lys Val 3825 3830 <210> SEQ ID NO 5 <400> SEQUENCE: 5 000 <210> SEQ ID NO 6 <400> SEQUENCE: 6 000 <210> SEQ ID NO 7 <211> LENGTH: 12792 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 7 atgatttaca ggaagaccat gtactcagct gcagcttcta aatccagaac gatttgcacg 60 tcttatcaag gaagtaatga atacattctg gcctggcaga gaattgattg ttcaatggta 120 tccatttgat gaaaacagaa atcacccatc tgtttcatgg cttaagatgg tttggaaaaa 180 tctttatata catttttcag aggatttgac tttatttgat gagatgccac ttatccccag 240 aactatacta gaggaaggtc agacatgtgt ggaactcatt agactcagga ttccatcgtt 300 agtcatttta gacgatgaat ctgaagcaca gcttccagaa tttttagcag acattgtaca 360 aaaacttgga gggtttgtcc ttaaaaaatt agatgcatct atacaacatc cgcttattaa 420 aaaatatatt cattcaccat taccaagtgc tgttttgcag ataatggaga agatgccatt 480 gcagaaattg tgtaatcaaa taacttcgct acttccaaca cacaaagatg ccctgaggaa 540 gttcttggct agtttaaccg atagcagtga gaaagagaaa agaattattc aagaattggc 600 aatattcaag cgcattaacc attcttctga tcagggaatt tcctcttata caaaattgaa 660 aggttgtaaa gtcttacacc atactgccaa actcccagca gatctgcgac tttctatttc 720 agtaatagac agtagtgatg aagctactat tcgtctggca aacatgttga aaatagaaca 780 gttaaagacc actagctgct taaagcttgt tttaaaagat attgaaaatg cattttattc 840 acatgaagag gtaacacagc ttatgttatg ggtccttgag aatctatctt ctcttaaaaa 900 tgagaatcca aatgtgcttg agtggttaac accattaaaa ttcatccaga tatcacagga 960 acagatggta tcagctggtg aactctttga ccctgatata gaagtactaa aggatctctt 1020 ttgtaatgaa gaaggaacct atttcccacc ctcagttttt acctcaccag atattcttca 1080 ctccttaaga cagattggtt taaaaaacga agccagtctc aaagaaaagg atgttgtgca 1140 agtggcaaaa aaaattgaag ccttacaggt cggtgcttgt cctgatcaag atgttcttct 1200 gaagaaagcc aaaaccctct tactggtttt aaataagaat cacacactgt tgcaatcatc 1260 tgaaggaaag atgacattga agaaaataaa atgggttcca gcctgcaagg aaaggcctcc 1320 aaattatcca ggctctttgg tctggaaagg agatctctgt aatctctgtg caccaccaga 1380 tatgtgtgat gtaggccatg caattctcat tggctcctca cttcctcttg ttgaaagtat 1440 ccatgtaaac ctggaaaaag cattagggat cttcacaaaa cctagcctta gtgctgtctt 1500 aaaacacttt aaaattgttg ttgattggta ttcttcaaaa acctttagtg atgaagacta 1560 ctatcaattc cagcatattt tgcttgagat ttacggattc atgcatgatc atctaaatga 1620 agggaaagat tcttttagag ccttaaaatt tccatgggtt tggactggca aaaagttttg 1680 tccacttgcc caggctgtga ttaaaccaat ccatgatctt gaccttcagc cttatttgca 1740 taatgtacct aaaaccatgg caaaattcca ccaactattt aaggtctgtg gttcaataga 1800 ggagttgaca tcagatcata tttccatggt tattcagaag atatatctca aaagtgacca 1860 agatctcagt gaacaagaaa gcaaacaaaa tcttcatctt atgttgaata ttatcagatg 1920 gctgtatagc aatcagattc cagcaagccc caacacacca gttcctatac atcatagcaa 1980 aaatccttct aaacttatca tgaagccaat tcacgaatgc tgttattgtg acattaaagt 2040 tgatgacctt aatgacttac ttgaagattc tgtggaacca atcattttgg tgcatgagga 2100 catacccatg aaaactgcag aatggctaaa agttccatgc cttagtacaa gactgataaa 2160 tcctgaaaac atgggatttg agcagtcagg acaaagagag ccacttactg taagaattaa 2220 aaatattctg gaagaatacc cttcagtgtc agatattttt aaagaactac ttcaaaacgc 2280 tgatgatgca aatgcaacag aatgcagttt cttgattgat atgagaagaa atatggacat 2340 aagagagaat ctcctagacc cagggatggc agcttgtcat ggacctgctt tgtggtcatt 2400 caacaattct caattctcag attcagattt tgtgaacata actaggttag gagaatcttt 2460 aaaaagggga gaagttgaca aagttggaaa atttggtctt ggatttaatt ctgtgtacca 2520 tatcactgac attcccatca ttatgagtcg ggaattcatg ataatgttcg atccaaacat 2580 aaatcatatc agtaaacaca ttaaagacaa atccaatcct gggatcaaaa ttaattggag 2640 taaacaacag aaaagactta gaaaatttcc taatcagttc aaaccattta tagatgtatt 2700 tggctgtcag ttacctttga ctgtagaagc accttacagc tataatggaa cccttttccg 2760 actgtccttt agaactcaac aggaagcaaa agtgagtgaa gttagtagta cgtgctacaa 2820 tacagcagat atttattctc ttgtggatga atttagtctc tgtggacaca ggcttatcat 2880 tttcactcag agtgtaaagt caatgtattt gaagtacttg aaaattgagg aaaccaaccc 2940 cagtttagca caagatacag taataattaa aaaaaaatcc tgctcttcca aagcattgaa 3000 cacacctgtc ttaagtgttt taaaagaggc tgctaagctc atgaagactt gcagcagcag 3060 taataaaaag cttcccagtg atgaaccaaa gtcatcttgc attcttcaga tcacagtgga 3120 agaatttcac catgtgttca gaaggattgc tgatttacag tcgccacttt ttagaggtcc 3180 agatgatgac ccagctgctc tctttgaaat ggctaagtct ggccaatcaa aaaagccatc 3240 agatgagttg tcacagaaaa cagtagagtg taccacgtgg cttctgtgta cttgcatgga 3300 cacaggagag gctctgaagt tttccctgag tgagagtgga agaagactag gactggttcc 3360 atgtggggca gtaggagttc agctgtcaga aatccaggac cagaagtgga cagtgaaacc 3420 acacattgga gaggtgtttt gctatttacc tttacgaata aaaacaggct tgccagttca 3480 tatcaatggg tgctttgctg ttacatcaaa taggaaagaa atctggaaaa cagatacaaa 3540 aggacgatgg aataccacgt tcatgagaca tgttattgtg aaagcttact tacaggtact 3600 gagtgtctta cgggacctgg ccactagtgg ggagctaatg gattatactt actatgcagt 3660 atggcccgat cctgatttag ttcatgatga tttttctgta atttgccaag gattttatga 3720 agatatagct catggaaaag ggaaagaact gaccaaagtc ttctctgatg gatctacttg 3780 ggtttccatg aagaacgtaa gatttctaga tgactctata cttaaaagaa gagatgttgg 3840 ttcagcagcc ttcaagatat ttttgaaata cctcaagaag actgggtcca aaaacctttg 3900 tgctgttgaa cttccttctt cggtaaaatt aggatttgaa gaagctggct gcaaacagat 3960 actacttgaa aacacatttt cagagaaaca gtttttttct gaagtgtttt ttccaaatat 4020 tcaagaaatt gaagcagaac ttagagatcc tttaatgatc tttgttctaa atgaaaaagt 4080 tgatgagttc tcgggagttc ttcgtgttac tccatgtatt ccttgttcct tggaggggca 4140 tcctttggtt ttgccatcaa gattgatcca ccccgaagga cgagttgcaa agttatttga 4200 tattaaagat gggagattcc cttatggttc tactcaggat tatctcaatc ctattatttt 4260 gattaaacta gttcagttag gtatggcaaa agatgatatt ttatgggatg atatgctaga 4320 acgtgcagtg tcagtagctg aaattaataa aagtgatcat gttgctgcat gcctaagaag 4380 tagtatctta ttgagtctta tcgatgagaa actaaaaata agggatccta gagcaaagga 4440 ttttgctgca aaatatcaaa caatccgctt ccttccattt ctgacaaaac cagcaggttt 4500 ttctttggac tggaaaggca acagttttaa gcctgaaacc atgtttgcag caactgacct 4560 ttatacagct gaacatcaag atatagtttg tcttttgcaa ccaattctaa atgaaaattc 4620 ccattctttt agaggttgtg gttcagtgtc attggctgtt aaagagtttt tgggattact 4680 caagaagcca acagttgatc tggttataaa ccaattgaaa gaagtagcaa aatcagttga 4740 tgatggaatt acactgtacc aggagaatat caccaatgct tgctacaaat accttcatga 4800 agccttgatg caaaatgaaa tcactaagat gtcaattatt gataagttaa aaccctttag 4860 cttcattcta gttgagaatg catatgttga ctcagaaaag gtttcttttc atttaaattt 4920 tgaggcggca ccataccttt atcagttgcc taataagtat aaaaataatt tccgcgaact 4980 ttttgaaacc gtgggtgtga ggcagtcatg cactgttgaa gattttgctc ttgttttgga 5040 atctattgat caagaaagag gaacaaagca aataacagaa gagaattttc agctttgccg 5100 acgaataatc agtgaaggaa tatggagtct cattagagaa aagaaacaag aattttgtga 5160 gaaaaattat ggcaagatat tattgccaga tactaatctt atgcttctcc ctgctaaatc 5220 gttatgctac aatgattgcc cttggataaa agtaaaggat accactgtaa aatattgtca 5280 tgctgacata cccagggaag tagcagtaaa actaggagca gtcccaaagc gacacaaagc 5340 cttagaaaga tatgcatcca atgtctgttt tacaacactt ggcacagaat ttgggcagaa 5400 agaaaaattg accagcagaa ttaagagcat ccttaatgca tatccttctg aaaaggaaat 5460 gttgaaagag cttcttcaaa atgctgatga tgcaaaggcg acagaaatct gttttgtgtt 5520 tgatcctaga cagcatccag ttgatagaat atttgatgat aagtgggccc cattgcaagg 5580 gccagcactt tgtgtgtaca acaaccagcc atttacagaa gatgatgtta gaggaattca 5640 gaatcttgga aaaggcacga aagagggaaa tccttataaa actggacagt atggaatagg 5700 attcaattct gtgtatcata tcacagactg cccatctttt atttctggca atgacatcct 5760 gtgtattttt gatcctcatg ccagatatgc accaggggcc acatccatta gtcccggacg 5820 catgtttaga gatttggatg cagattttag gacacagttc tcagatgttc tggatcttta 5880 tctgggaacc cattttaaac tggataattg cacaatgttc agatttcctc ttcgtaatgc 5940 agaaatggca aaagtttcgg aaatttcgtc tgttccagca tcagacagaa tggtccagaa 6000 tcttttggac aaactgcgct cagatggggc agaacttcta atgtttctta atcacatgga 6060 aaaaatttct atttgtgaaa tagataagag tactggagct ctaaatgtgc tgtattcagt 6120 aaagggcaaa atcacagatg gagacagatt gaaaaggaaa caatttcatg catctgtaat 6180 tgatagtgtt actaaaaaga ggcagctcaa agacatacca gttcaacaaa taacctatac 6240 tatggatact gaggactctg aaggaaatct tactacgtgg ctaatttgta atagatcagg 6300 cttttcaagt atggagaaag tatctaaaag tgtcatatca gctcacaaga accaagatat 6360 tactcttttc ccacgtggtg gagtagctgc ctgcattact cacaactata aaaaacccca 6420 tagggccttc tgttttttgc ctctttcttt ggagactggg ctgccatttc atgtgaatgg 6480 ccactttgca ctggattcag ccagaaggaa cctgtggcgt gatgataatg gagttggtgt 6540 tcgaagtgac tggaataaca gtttaatgac agcattaata gctcctgcat atgtgaattg 6600 ctaatacagt taaaaaaacg gtatttccct ggttctgatc caacattatc agtgttacag 6660 aacaccccta ttcatgttgt aaaggacact ttaaagaagt ttttatcgtt tttcccagtt 6720 aaccgtcttg atctacagcc agatttatat tgtctagtga aagcacttta caattgcatt 6780 cacgaagaca tgaaacgtct tttacctgtt gtgcgggctc caaatattga tggctctgac 6840 ttgcactctg cagttataat tacttggatc aatatgtcta cttctaataa aactagacca 6900 ttttttgaca atttactaca ggatgaatta caacacctta aaaatgcaga ttataatatc 6960 accacacgca aaacagtagc agagaatgtc tataggctga aacatctcct tttagaaatt 7020 ggtttcaact tggtttataa ctgtgatgaa actgctaatc tttaccactg tcttatagat 7080 gcagatattc ctgttagtta tgtgacccct gctgatatca gatctttttt aatgacattt 7140 tcctctcctg acactaattg ccatattggg aagctgcctt gtcgtctgca gcagactaat 7200 ctaaaacttt ttcatagttt aaaactttta gttgattatt gttttaaaga tgcagaagaa 7260 aatgagattg aagttgaggg attgcccctt ctcatcacac tggacagtgt tttgcaaact 7320 tttgatgcaa aacgacccaa gtttctaaca acatatcatg aattgattcc atcccgcaaa 7380 gacttgttta tgaatacatt atatttgaaa tatagtaata ttttattgaa ctgtaaagtt 7440 gcaaaagtgt ttgacatttc cagctttgct gatttgttat cctctgtgtt gcctcgagaa 7500 tataagacca aaagttgcac aaagtggaaa gacaattttg caagtgagtc ttggcttaag 7560 aatgcatggc attttattag tgaatctgta agtgtgaaag aagatcagga agaaacaaaa 7620 ccaacatttg acattgttgt tgatactcta aaagactggg cattgcttcc aggaacaaag 7680 tttactgttt cagccaacca gcttgtggtt cctgaaggag atgttctgct tcctctcagc 7740 cttatgcaca ttgcagtttt tccaaatgcc cagagtgata aagtttttca tgctctaatg 7800 aaagccggct gtattcagct tgctttgaac aaaatctgtt ccaaagacag tgcatttgtt 7860 cctttgttgt catgtcacac agcaaatata gagagcccca caagcatctt gaaggctcta 7920 cattatatgg tccaaacttc aacatttaga gcagaaaaat tagtagaaaa tgattttgag 7980 gcacttttga tgtatttcaa ctgcaatttg aatcatttga tgtcccaaga tgatataaaa 8040 attctaaagt cacttccgtg ctataaatcc atcagtggcc gctatgtaag cattggaaaa 8100 tttggaacat gctacgtact tacaaaaagt atcccttcag ctgaagtgga gaaatggaca 8160 caatcatcat catctgcatt tcttgaagaa aaaatacact taaaagaact atatgaggtg 8220 attggttgtg tacctgtaga tgatcttgag gtatatttga aacacctctt accaaaaatt 8280 gaaaatctct cttatgatgc aaaattagag cacttgatct accttaagaa tagattatca 8340 agtgctgagg aattatcaga gattaaggaa caactttttg aaaaactgga aagtttattg 8400 ataatccatg atgctaacag tagactaaag caagcaaagc atttctatga tagaactgtg 8460 agagtttttg aagttatgct tcctgaaaaa ttgtttattc ctaatgattt ctttaagaaa 8520 ttggaacaac ttataaaacc caaaaatcat gttacattta tgacatcctg ggtggaattc 8580 ttaagaaata ttggactaaa atacatactt tctcagcagc agttgttaca gtttgctaag 8640 gaaatcagtg tgagggctaa tacagaaaac tggtccaaag aaacattgca aaatacagtt 8700 gatatccttc tgcatcatat attccaagaa cgaatggatt tgttatctgg aaattttctg 8760 aaagaactat ctttaatacc attcttatgt cctgagcggg cccccgcgga attcattaga 8820 tttcatcctc aatatcaaga ggtaaatgga acacttcctc ttataaagtt caatggagca 8880 caggtaaatc caaaattcaa gcaatgtgat gtactccagc tgttatggac atcctgccct 8940 attcttccag agaaagctac acccttaagc attaaagaac aagaaggtag tgaccttggt 9000 ccacaagaac agcttgaaca agttttaaat atgcttaatg ttaacctgga tcctcctctt 9060 gataaggtaa tcaataactg cagaaacata tgcaacataa cgacgttgga tgaagaaatg 9120 gtaaaaacta gagcaaaagt cttaaggagc atatatgaat tcctcagtgc agaaaaaagg 9180 gaatttcgtt ttcagttgcg aggggttgct tttgtgatgg tagaagatgg ttggaaactt 9240 ctgaagcctg aggaggtagt cataaaccta gaatatgaat ctgattttaa accttatttg 9300 tacaagctac ctttagaact tggcacattt caccagttgt tcaaacactt aggtactgaa 9360 gatattattt caactaagca atatgttgaa gtgttgagcc gcatatttaa aaattctgag 9420 ggcaaacaat tagatcctaa tgaaatgcgt acagttaaga gagtagtttc tggtctgttc 9480 aggagtctac agaatgattc agtcaaggtg aggagtgatc tcgagaatgt acgagacctt 9540 gcgctttacc tcccaagcca ggatggtaga ttggtaaagt caagcatctt agtgtttgac 9600 gatgcgccac attataaaag tagaatccag gggaatattg gtgtgcaaat gttagttgat 9660 ctcagccagt gctacttagg gaaagaccat ggatttcaca ctaagttgat aatgctcttt 9720 cctcaaaaac ttagacctcg attattgagc agtatacttg aagaacaatt agatgaagag 9780 actcccaaag tttgtcagtt tggagcgttg tgttctcttc aaggaagatt gcagttactc 9840 ttgtcttctg aacagttcat tacaggactg attagaatta tgaagcatga aaatgataat 9900 gcttttctgg ccaatgaaga aaaagccata agactttgca aagccctaag agaaggattg 9960 aaagtatcct gctttgaaaa gcttcaaaca acattaagag ttaaaggttt taatcctatt 10020 ccccacagca gaagtgaaac ttttgctttt ttgaagcgat ttggtaatgc agtcatcttg 10080 ctctacattc aacattcaga cagtaaagac attaatttcc tgttagcact ggcaatgact 10140 cttaaatcag caactgacaa tttgatttct gacacttcat atttaattgc tatgctagga 10200 tgcaatgata tttacaggat tggtgagaaa cttgacagtt taggagtgaa atatgactct 10260 tcggagccat caaaactgga acttccaatg cctggcacac caattcctgc tgaaattcat 10320 tacactctgc ttatggaccc aatgaatgtt ttttacccgg gagaatatgt tgggtacctt 10380 gttgatgctg aaggtggtga tatctatgga tcataccagc caacatacac atatgcaatt 10440 attgtacaag aagttgaaag agaagatgct gacaattcta gttttctagg aaagatatat 10500 cagatagata ttggttatag tgaatataaa atagttagct ctcttgatct gtataagttt 10560 tcaagacctg aggaaagctc tcaaagcagg gacagtgctc cttctacacc aaccagcccc 10620 actgagttcc tcacccctgg cctgagaagc attcctcctc ttttctctgg tagagagagc 10680 cacaagactt cttccaaaca tcagtccccc aaaaagctta aggttaattc tttaccagaa 10740 atcttaaaag aagtgacatc tgtggtggag caagcatgga agcttccaga atcggaacga 10800 aaaaagatta ttaggcggtt gtatttgaaa tggcatcctg acaaaaatcc agagaaccat 10860 gacattgcca atgaagtttt taaacatttg cagaatgaaa tcaacagatt agaaaaacag 10920 gcttttctag atcaaaatgc agacagggcc tccagacgaa cattttcaac ctcagcatcc 10980 cgatttcagt cagacaaata ctcatttcag agattctata cttcatggaa tcaagaagca 11040 acgagccata aatctgaaag acagcaacag aacaaagaaa aatgcccccc ttcagccgga 11100 cagacttact ctcaaaggtt ctttgttcct cccactttca agtcggttgg caatccagtg 11160 gaagcacgca gatggctaag acaagccaga gcaaacttct cagctgccag gaatgacctt 11220 cataaaaatg ccaatgagtg ggtgtgcttt aaatgttacc tttctaccaa gttagctttg 11280 attgcagctg actatgctgt gaggggaaag tctgataaag atgtaaaacc aactgcactt 11340 gctcagaaaa tagaggaata tagtcagcaa cttgaaggac tgacaaatga tgttcacaca 11400 ttggaagctt atggtgtaga cagtttaaaa acaagatacc ctgatttgct tccctttcct 11460 cagatcccaa atgacaggtt cacttctgag gttgctatga gggtgatgga atgtactgcc 11520 tgtatcataa taaaacttga aaattttatg caacaaaaag tgtgaagata tttaacgaaa 11580 aaaaaggtag atcttgaatg tgttgtagca cgaataaatt gctgtacttc attaagcttc 11640 attgccaatt agctaggaat tgttaagcac attgcagatt gttcttggag aattctggag 11700 ttgttatgaa catgaatacc aacggaaaac cttaactgaa tctaaaagaa aactattttg 11760 aagatggtgg tgagctgcaa aatagctgga tggatttgaa tgattgggat gatacatcat 11820 tgaactgcac tttatataac caaagcttag cagtttgtta gataagagtc tatgtatgtc 11880 tctggttagg atgaagttaa ttttatgttt ttaacatggt atttttgaag gagctaatga 11940 aacactggac atataattgg tttaaacata aggggaatta agtctttgta gtctgtcatt 12000 tttttaagtg gatcctcttg gatgcgttat tttctcatca gctggctctg atcatgaatt 12060 tgttgtaatt ttatgttgta ctcagtgcat ttaagaaatg gtagagtatt ttaatcctat 12120 tacttgacta agagtgtgaa ggtagtactt tttagagtgc actgagtgca ctttacatct 12180 ttatttaaat ttttttttaa catcttatgt ttacaggctt cctgtttgat gaagatagca 12240 acggaaaact caaaatggtg gcagttctta ttaccagttg ttagtattgt ttctggaaac 12300 tgcttgccaa gacaacattt attaactgtt agaacacttg ctttatgttt gtgtgtacat 12360 attttccaca aatgttataa tttatatagt gtggttgaac aggatgcaat cttttgttgt 12420 ctaaaggtgc tgcagttaaa aaaaaaacaa ccttttcttt caatatggca tgtagtggag 12480 tttttttaac tttaaaaaca tcaaaaattg ttaaaatcat tgtgttatct agtagtttat 12540 aattatcggc ttatatttcc ccatgaatga tcagaactga catttaattc atgtttgtct 12600 cgccatgctt ctttacttta acatatttct tttgcagaat gtaaaaggta atgataatta 12660 gtttatataa gtgtactggc tgtaaatgat gctaaatata ctttatgcaa ttaagggctt 12720 acagaacatg ttgaaacttt ttttactttt attgggaata aggaatgttt gcacctccac 12780 attttattgc tt 12792 <210> SEQ ID NO 8 <211> LENGTH: 2175 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 8 Met Asn Thr Phe Trp Pro Gly Arg Glu Leu Ile Val Gln Trp Tyr Pro 1 5 10 15 Phe Asp Glu Asn Arg Asn His Pro Ser Val Ser Trp Leu Lys Met Val 20 25 30 Trp Lys Asn Leu Tyr Ile His Phe Ser Glu Asp Leu Thr Leu Phe Asp 35 40 45 Glu Met Pro Leu Ile Pro Arg Thr Ile Leu Glu Glu Gly Gln Thr Cys 50 55 60 Val Glu Leu Ile Arg Leu Arg Ile Pro Ser Leu Val Ile Leu Asp Asp 65 70 75 80 Glu Ser Glu Ala Gln Leu Pro Glu Phe Leu Ala Asp Ile Val Gln Lys 85 90 95 Leu Gly Gly Phe Val Leu Lys Lys Leu Asp Ala Ser Ile Gln His Pro 100 105 110 Leu Ile Lys Lys Tyr Ile His Ser Pro Leu Pro Ser Ala Val Leu Gln 115 120 125 Ile Met Glu Lys Met Pro Leu Gln Lys Leu Cys Asn Gln Ile Thr Ser 130 135 140 Leu Leu Pro Thr His Lys Asp Ala Leu Arg Lys Phe Leu Ala Ser Leu 145 150 155 160 Thr Asp Ser Ser Glu Lys Glu Lys Arg Ile Ile Gln Glu Leu Ala Ile 165 170 175 Phe Lys Arg Ile Asn His Ser Ser Asp Gln Gly Ile Ser Ser Tyr Thr 180 185 190 Lys Leu Lys Gly Cys Lys Val Leu His His Thr Ala Lys Leu Pro Ala 195 200 205 Asp Leu Arg Leu Ser Ile Ser Val Ile Asp Ser Ser Asp Glu Ala Thr 210 215 220 Ile Arg Leu Ala Asn Met Leu Lys Ile Glu Gln Leu Lys Thr Thr Ser 225 230 235 240 Cys Leu Lys Leu Val Leu Lys Asp Ile Glu Asn Ala Phe Tyr Ser His 245 250 255 Glu Glu Val Thr Gln Leu Met Leu Trp Val Leu Glu Asn Leu Ser Ser 260 265 270 Leu Lys Asn Glu Asn Pro Asn Val Leu Glu Trp Leu Thr Pro Leu Lys 275 280 285 Phe Ile Gln Ile Ser Gln Glu Gln Met Val Ser Ala Gly Glu Leu Phe 290 295 300 Asp Pro Asp Ile Glu Val Leu Lys Asp Leu Phe Cys Asn Glu Glu Gly 305 310 315 320 Thr Tyr Phe Pro Pro Ser Val Phe Thr Ser Pro Asp Ile Leu His Ser 325 330 335 Leu Arg Gln Ile Gly Leu Lys Asn Glu Ala Ser Leu Lys Glu Lys Asp 340 345 350 Val Val Gln Val Ala Lys Lys Ile Glu Ala Leu Gln Val Gly Ala Cys 355 360 365 Pro Asp Gln Asp Val Leu Leu Lys Lys Ala Lys Thr Leu Leu Leu Val 370 375 380 Leu Asn Lys Asn His Thr Leu Leu Gln Ser Ser Glu Gly Lys Met Thr 385 390 395 400 Leu Lys Lys Ile Lys Trp Val Pro Ala Cys Lys Glu Arg Pro Pro Asn 405 410 415 Tyr Pro Gly Ser Leu Val Trp Lys Gly Asp Leu Cys Asn Leu Cys Ala 420 425 430 Pro Pro Asp Met Cys Asp Val Gly His Ala Ile Leu Ile Gly Ser Ser 435 440 445 Leu Pro Leu Val Glu Ser Ile His Val Asn Leu Glu Lys Ala Leu Gly 450 455 460 Ile Phe Thr Lys Pro Ser Leu Ser Ala Val Leu Lys His Phe Lys Ile 465 470 475 480 Val Val Asp Trp Tyr Ser Ser Lys Thr Phe Ser Asp Glu Asp Tyr Tyr 485 490 495 Gln Phe Gln His Ile Leu Leu Glu Ile Tyr Gly Phe Met His Asp His 500 505 510 Leu Asn Glu Gly Lys Asp Ser Phe Arg Ala Leu Lys Phe Pro Trp Val 515 520 525 Trp Thr Gly Lys Lys Phe Cys Pro Leu Ala Gln Ala Val Ile Lys Pro 530 535 540 Ile His Asp Leu Asp Leu Gln Pro Tyr Leu His Asn Val Pro Lys Thr 545 550 555 560 Met Ala Lys Phe His Gln Leu Phe Lys Val Cys Gly Ser Ile Glu Glu 565 570 575 Leu Thr Ser Asp His Ile Ser Met Val Ile Gln Lys Ile Tyr Leu Lys 580 585 590 Ser Asp Gln Asp Leu Ser Glu Gln Glu Ser Lys Gln Asn Leu His Leu 595 600 605 Met Leu Asn Ile Ile Arg Trp Leu Tyr Ser Asn Gln Ile Pro Ala Ser 610 615 620 Pro Asn Thr Pro Val Pro Ile His His Ser Lys Asn Pro Ser Lys Leu 625 630 635 640 Ile Met Lys Pro Ile His Glu Cys Cys Tyr Cys Asp Ile Lys Val Asp 645 650 655 Asp Leu Asn Asp Leu Leu Glu Asp Ser Val Glu Pro Ile Ile Leu Val 660 665 670 His Glu Asp Ile Pro Met Lys Thr Ala Glu Trp Leu Lys Val Pro Cys 675 680 685 Leu Ser Thr Arg Leu Ile Asn Pro Glu Asn Met Gly Phe Glu Gln Ser 690 695 700 Gly Gln Arg Glu Pro Leu Thr Val Arg Ile Lys Asn Ile Leu Glu Glu 705 710 715 720 Tyr Pro Ser Val Ser Asp Ile Phe Lys Glu Leu Leu Gln Asn Ala Asp 725 730 735 Asp Ala Asn Ala Thr Glu Cys Ser Phe Leu Ile Asp Met Arg Arg Asn 740 745 750 Met Asp Ile Arg Glu Asn Leu Leu Asp Pro Gly Met Ala Ala Cys His 755 760 765 Gly Pro Ala Leu Trp Ser Phe Asn Asn Ser Gln Phe Ser Asp Ser Asp 770 775 780 Phe Val Asn Ile Thr Arg Leu Gly Glu Ser Leu Lys Arg Gly Glu Val 785 790 795 800 Asp Lys Val Gly Lys Phe Gly Leu Gly Phe Asn Ser Val Tyr His Ile 805 810 815 Thr Asp Ile Pro Ile Ile Met Ser Arg Glu Phe Met Ile Met Phe Asp 820 825 830 Pro Asn Ile Asn His Ile Ser Lys His Ile Lys Asp Lys Ser Asn Pro 835 840 845 Gly Ile Lys Ile Asn Trp Ser Lys Gln Gln Lys Arg Leu Arg Lys Phe 850 855 860 Pro Asn Gln Phe Lys Pro Phe Ile Asp Val Phe Gly Cys Gln Leu Pro 865 870 875 880 Leu Thr Val Glu Ala Pro Tyr Ser Tyr Asn Gly Thr Leu Phe Arg Leu 885 890 895 Ser Phe Arg Thr Gln Gln Glu Ala Lys Val Ser Glu Val Ser Ser Thr 900 905 910 Cys Tyr Asn Thr Ala Asp Ile Tyr Ser Leu Val Asp Glu Phe Ser Leu 915 920 925 Cys Gly His Arg Leu Ile Ile Phe Thr Gln Ser Val Lys Ser Met Tyr 930 935 940 Leu Lys Tyr Leu Lys Ile Glu Glu Thr Asn Pro Ser Leu Ala Gln Asp 945 950 955 960 Thr Val Ile Ile Lys Lys Lys Ser Cys Ser Ser Lys Ala Leu Asn Thr 965 970 975 Pro Val Leu Ser Val Leu Lys Glu Ala Ala Lys Leu Met Lys Thr Cys 980 985 990 Ser Ser Ser Asn Lys Lys Leu Pro Ser Asp Glu Pro Lys Ser Ser Cys 995 1000 1005 Ile Leu Gln Ile Thr Val Glu Glu Phe His His Val Phe Arg Arg Ile 1010 1015 1020 Ala Asp Leu Gln Ser Pro Leu Phe Arg Gly Pro Asp Asp Asp Pro Ala 1025 1030 1035 1040 Ala Leu Phe Glu Met Ala Lys Ser Gly Gln Ser Lys Lys Pro Ser Asp 1045 1050 1055 Glu Leu Ser Gln Lys Thr Val Glu Cys Thr Thr Trp Leu Leu Cys Thr 1060 1065 1070 Cys Met Asp Thr Gly Glu Ala Leu Lys Phe Ser Leu Ser Glu Ser Gly 1075 1080 1085 Arg Arg Leu Gly Leu Val Pro Cys Gly Ala Val Gly Val Gln Leu Ser 1090 1095 1100 Glu Ile Gln Asp Gln Lys Trp Thr Val Lys Pro His Ile Gly Glu Val 1105 1110 1115 1120 Phe Cys Tyr Leu Pro Leu Arg Ile Lys Thr Gly Leu Pro Val His Ile 1125 1130 1135 Asn Gly Cys Phe Ala Val Thr Ser Asn Arg Lys Glu Ile Trp Lys Thr 1140 1145 1150 Asp Thr Lys Gly Arg Trp Asn Thr Thr Phe Met Arg His Val Ile Val 1155 1160 1165 Lys Ala Tyr Leu Gln Val Leu Ser Val Leu Arg Asp Leu Ala Thr Ser 1170 1175 1180 Gly Glu Leu Met Asp Tyr Thr Tyr Tyr Ala Val Trp Pro Asp Pro Asp 1185 1190 1195 1200 Leu Val His Asp Asp Phe Ser Val Ile Cys Gln Gly Phe Tyr Glu Asp 1205 1210 1215 Ile Ala His Gly Lys Gly Lys Glu Leu Thr Lys Val Phe Ser Asp Gly 1220 1225 1230 Ser Thr Trp Val Ser Met Lys Asn Val Arg Phe Leu Asp Asp Ser Ile 1235 1240 1245 Leu Lys Arg Arg Asp Val Gly Ser Ala Ala Phe Lys Ile Phe Leu Lys 1250 1255 1260 Tyr Leu Lys Lys Thr Gly Ser Lys Asn Leu Cys Ala Val Glu Leu Pro 1265 1270 1275 1280 Ser Ser Val Lys Leu Gly Phe Glu Glu Ala Gly Cys Lys Gln Ile Leu 1285 1290 1295 Leu Glu Asn Thr Phe Ser Glu Lys Gln Phe Phe Ser Glu Val Phe Phe 1300 1305 1310 Pro Asn Ile Gln Glu Ile Glu Ala Glu Leu Arg Asp Pro Leu Met Ile 1315 1320 1325 Phe Val Leu Asn Glu Lys Val Asp Glu Phe Ser Gly Val Leu Arg Val 1330 1335 1340 Thr Pro Cys Ile Pro Cys Ser Leu Glu Gly His Pro Leu Val Leu Pro 1345 1350 1355 1360 Ser Arg Leu Ile His Pro Glu Gly Arg Val Ala Lys Leu Phe Asp Ile 1365 1370 1375 Lys Asp Gly Arg Phe Pro Tyr Gly Ser Thr Gln Asp Tyr Leu Asn Pro 1380 1385 1390 Ile Ile Leu Ile Lys Leu Val Gln Leu Gly Met Ala Lys Asp Asp Ile 1395 1400 1405 Leu Trp Asp Asp Met Leu Glu Arg Ala Val Ser Val Ala Glu Ile Asn 1410 1415 1420 Lys Ser Asp His Val Ala Ala Cys Leu Arg Ser Ser Ile Leu Leu Ser 1425 1430 1435 1440 Leu Ile Asp Glu Lys Leu Lys Ile Arg Asp Pro Arg Ala Lys Asp Phe 1445 1450 1455 Ala Ala Lys Tyr Gln Thr Ile Arg Phe Leu Pro Phe Leu Thr Lys Pro 1460 1465 1470 Ala Gly Phe Ser Leu Asp Trp Lys Gly Asn Ser Phe Lys Pro Glu Thr 1475 1480 1485 Met Phe Ala Ala Thr Asp Leu Tyr Thr Ala Glu His Gln Asp Ile Val 1490 1495 1500 Cys Leu Leu Gln Pro Ile Leu Asn Glu Asn Ser His Ser Phe Arg Gly 1505 1510 1515 1520 Cys Gly Ser Val Ser Leu Ala Val Lys Glu Phe Leu Gly Leu Leu Lys 1525 1530 1535 Lys Pro Thr Val Asp Leu Val Ile Asn Gln Leu Lys Glu Val Ala Lys 1540 1545 1550 Ser Val Asp Asp Gly Ile Thr Leu Tyr Gln Glu Asn Ile Thr Asn Ala 1555 1560 1565 Cys Tyr Lys Tyr Leu His Glu Ala Leu Met Gln Asn Glu Ile Thr Lys 1570 1575 1580 Met Ser Ile Ile Asp Lys Leu Lys Pro Phe Ser Phe Ile Leu Val Glu 1585 1590 1595 1600 Asn Ala Tyr Val Asp Ser Glu Lys Val Ser Phe His Leu Asn Phe Glu 1605 1610 1615 Ala Ala Pro Tyr Leu Tyr Gln Leu Pro Asn Lys Tyr Lys Asn Asn Phe 1620 1625 1630 Arg Glu Leu Phe Glu Thr Val Gly Val Arg Gln Ser Cys Thr Val Glu 1635 1640 1645 Asp Phe Ala Leu Val Leu Glu Ser Ile Asp Gln Glu Arg Gly Thr Lys 1650 1655 1660 Gln Ile Thr Glu Glu Asn Phe Gln Leu Cys Arg Arg Ile Ile Ser Glu 1665 1670 1675 1680 Gly Ile Trp Ser Leu Ile Arg Glu Lys Lys Gln Glu Phe Cys Glu Lys 1685 1690 1695 Asn Tyr Gly Lys Ile Leu Leu Pro Asp Thr Asn Leu Met Leu Leu Pro 1700 1705 1710 Ala Lys Ser Leu Cys Tyr Asn Asp Cys Pro Trp Ile Lys Val Lys Asp 1715 1720 1725 Thr Thr Val Lys Tyr Cys His Ala Asp Ile Pro Arg Glu Val Ala Val 1730 1735 1740 Lys Leu Gly Ala Val Pro Lys Arg His Lys Ala Leu Glu Arg Tyr Ala 1745 1750 1755 1760 Ser Asn Val Cys Phe Thr Thr Leu Gly Thr Glu Phe Gly Gln Lys Glu 1765 1770 1775 Lys Leu Thr Ser Arg Ile Lys Ser Ile Leu Asn Ala Tyr Pro Ser Glu 1780 1785 1790 Lys Glu Met Leu Lys Glu Leu Leu Gln Asn Ala Asp Asp Ala Lys Ala 1795 1800 1805 Thr Glu Ile Cys Phe Val Phe Asp Pro Arg Gln His Pro Val Asp Arg 1810 1815 1820 Ile Phe Asp Asp Lys Trp Ala Pro Leu Gln Gly Pro Ala Leu Cys Val 1825 1830 1835 1840 Tyr Asn Asn Gln Pro Phe Thr Glu Asp Asp Val Arg Gly Ile Gln Asn 1845 1850 1855 Leu Gly Lys Gly Thr Lys Glu Gly Asn Pro Tyr Lys Thr Gly Gln Tyr 1860 1865 1870 Gly Ile Gly Phe Asn Ser Val Tyr His Ile Thr Asp Cys Pro Ser Phe 1875 1880 1885 Ile Ser Gly Asn Asp Ile Leu Cys Ile Phe Asp Pro His Ala Arg Tyr 1890 1895 1900 Ala Pro Gly Ala Thr Ser Ile Ser Pro Gly Arg Met Phe Arg Asp Leu 1905 1910 1915 1920 Asp Ala Asp Phe Arg Thr Gln Phe Ser Asp Val Leu Asp Leu Tyr Leu 1925 1930 1935 Gly Thr His Phe Lys Leu Asp Asn Cys Thr Met Phe Arg Phe Pro Leu 1940 1945 1950 Arg Asn Ala Glu Met Ala Lys Val Ser Glu Ile Ser Ser Val Pro Ala 1955 1960 1965 Ser Asp Arg Met Val Gln Asn Leu Leu Asp Lys Leu Arg Ser Asp Gly 1970 1975 1980 Ala Glu Leu Leu Met Phe Leu Asn His Met Glu Lys Ile Ser Ile Cys 1985 1990 1995 2000 Glu Ile Asp Lys Ser Thr Gly Ala Leu Asn Val Leu Tyr Ser Val Lys 2005 2010 2015 Gly Lys Ile Thr Asp Gly Asp Arg Leu Lys Arg Lys Gln Phe His Ala 2020 2025 2030 Ser Val Ile Asp Ser Val Thr Lys Lys Arg Gln Leu Lys Asp Ile Pro 2035 2040 2045 Val Gln Gln Ile Thr Tyr Thr Met Asp Thr Glu Asp Ser Glu Gly Asn 2050 2055 2060 Leu Thr Thr Trp Leu Ile Cys Asn Arg Ser Gly Phe Ser Ser Met Glu 2065 2070 2075 2080 Lys Val Ser Lys Ser Val Ile Ser Ala His Lys Asn Gln Asp Ile Thr 2085 2090 2095 Leu Phe Pro Arg Gly Gly Val Ala Ala Cys Ile Thr His Asn Tyr Lys 2100 2105 2110 Lys Pro His Arg Ala Phe Cys Phe Leu Pro Leu Ser Leu Glu Thr Gly 2115 2120 2125 Leu Pro Phe His Val Asn Gly His Phe Ala Leu Asp Ser Ala Arg Arg 2130 2135 2140 Asn Leu Trp Arg Asp Asp Asn Gly Val Gly Val Arg Ser Asp Trp Asn 2145 2150 2155 2160 Asn Ser Leu Met Thr Ala Leu Ile Ala Pro Ala Tyr Val Asn Cys 2165 2170 2175 <210> SEQ ID NO 9 <211> LENGTH: 12717 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 9 atgaatacat tctggcctgg cagagaattg attgttcaat ggtatccatt tgatgaaaac 60 agaaatcacc catctgtttc atggcttaag atggtttgga aaaatcttta tatacatttt 120 tcagaggatt tgactttatt tgatgagatg ccacttatcc ccagaactat actagaggaa 180 ggtcagacat gtgtggaact cattagactc aggattccat cgttagtcat tttagacgat 240 gaatctgaag cacagcttcc agaattttta gcagacattg tacaaaaact tggagggttt 300 gtccttaaaa aattagatgc atctatacaa catccgctta ttaaaaaata tattcattca 360 ccattaccaa gtgctgtttt gcagataatg gagaagatgc cattgcagaa attgtgtaat 420 caaataactt cgctacttcc aacacacaaa gatgccctga ggaagttctt ggctagttta 480 accgatagca gtgagaaaga gaaaagaatt attcaagaat tggcaatatt caagcgcatt 540 aaccattctt ctgatcaggg aatttcctct tatacaaaat tgaaaggttg taaagtctta 600 caccatactg ccaaactccc agcagatctg cgactttcta tttcagtaat agacagtagt 660 gatgaagcta ctattcgtct ggcaaacatg ttgaaaatag aacagttaaa gaccactagc 720 tgcttaaagc ttgttttaaa agatattgaa aatgcatttt attcacatga agaggtaaca 780 cagcttatgt tatgggtcct tgagaatcta tcttctctta aaaatgagaa tccaaatgtg 840 cttgagtggt taacaccatt aaaattcatc cagatatcac aggaacagat ggtatcagct 900 ggtgaactct ttgaccctga tatagaagta ctaaaggatc tcttttgtaa tgaagaagga 960 acctatttcc caccctcagt ttttacctca ccagatattc ttcactcctt aagacagatt 1020 ggtttaaaaa acgaagccag tctcaaagaa aaggatgttg tgcaagtggc aaaaaaaatt 1080 gaagccttac aggtcggtgc ttgtcctgat caagatgttc ttctgaagaa agccaaaacc 1140 ctcttactgg ttttaaataa gaatcacaca ctgttgcaat catctgaagg aaagatgaca 1200 ttgaagaaaa taaaatgggt tccagcctgc aaggaaaggc ctccaaatta tccaggctct 1260 ttggtctgga aaggagatct ctgtaatctc tgtgcaccac cagatatgtg tgatgtaggc 1320 catgcaattc tcattggctc ctcacttcct cttgttgaaa gtatccatgt aaacctggaa 1380 aaagcattag ggatcttcac aaaacctagc cttagtgctg tcttaaaaca ctttaaaatt 1440 gttgttgatt ggtattcttc aaaaaccttt agtgatgaag actactatca attccagcat 1500 attttgcttg agatttacgg attcatgcat gatcatctaa atgaagggaa agattctttt 1560 agagccttaa aatttccatg ggtttggact ggcaaaaagt tttgtccact tgcccaggct 1620 gtgattaaac caatccatga tcttgacctt cagccttatt tgcataatgt acctaaaacc 1680 atggcaaaat tccaccaact atttaaggtc tgtggttcaa tagaggagtt gacatcagat 1740 catatttcca tggttattca gaagatatat ctcaaaagtg accaagatct cagtgaacaa 1800 gaaagcaaac aaaatcttca tcttatgttg aatattatca gatggctgta tagcaatcag 1860 attccagcaa gccccaacac accagttcct atacatcata gcaaaaatcc ttctaaactt 1920 atcatgaagc caattcacga atgctgttat tgtgacatta aagttgatga ccttaatgac 1980 ttacttgaag attctgtgga accaatcatt ttggtgcatg aggacatacc catgaaaact 2040 gcagaatggc taaaagttcc atgccttagt acaagactga taaatcctga aaacatggga 2100 tttgagcagt caggacaaag agagccactt actgtaagaa ttaaaaatat tctggaagaa 2160 tacccttcag tgtcagatat ttttaaagaa ctacttcaaa acgctgatga tgcaaatgca 2220 acagaatgca gtttcttgat tgatatgaga agaaatatgg acataagaga gaatctccta 2280 gacccaggga tggcagcttg tcatggacct gctttgtggt cattcaacaa ttctcaattc 2340 tcagattcag attttgtgaa cataactagg ttaggagaat ctttaaaaag gggagaagtt 2400 gacaaagttg gaaaatttgg tcttggattt aattctgtgt accatatcac tgacattccc 2460 atcattatga gtcgggaatt catgataatg ttcgatccaa acataaatca tatcagtaaa 2520 cacattaaag acaaatccaa tcctgggatc aaaattaatt ggagtaaaca acagaaaaga 2580 cttagaaaat ttcctaatca gttcaaacca tttatagatg tatttggctg tcagttacct 2640 ttgactgtag aagcacctta cagctataat ggaacccttt tccgactgtc ctttagaact 2700 caacaggaag caaaagtgag tgaagttagt agtacgtgct acaatacagc agatatttat 2760 tctcttgtgg atgaatttag tctctgtgga cacaggctta tcattttcac tcagagtgta 2820 aagtcaatgt atttgaagta cttgaaaatt gaggaaacca accccagttt agcacaagat 2880 acagtaataa ttaaaaaaaa atcctgctct tccaaagcat tgaacacacc tgtcttaagt 2940 gttttaaaag aggctgctaa gctcatgaag acttgcagca gcagtaataa aaagcttccc 3000 agtgatgaac caaagtcatc ttgcattctt cagatcacag tggaagaatt tcaccatgtg 3060 ttcagaagga ttgctgattt acagtcgcca ctttttagag gtccagatga tgacccagct 3120 gctctctttg aaatggctaa gtctggccaa tcaaaaaagc catcagatga gttgtcacag 3180 aaaacagtag agtgtaccac gtggcttctg tgtacttgca tggacacagg agaggctctg 3240 aagttttccc tgagtgagag tggaagaaga ctaggactgg ttccatgtgg ggcagtagga 3300 gttcagctgt cagaaatcca ggaccagaag tggacagtga aaccacacat tggagaggtg 3360 ttttgctatt tacctttacg aataaaaaca ggcttgccag ttcatatcaa tgggtgcttt 3420 gctgttacat caaataggaa agaaatctgg aaaacagata caaaaggacg atggaatacc 3480 acgttcatga gacatgttat tgtgaaagct tacttacagg tactgagtgt cttacgggac 3540 ctggccacta gtggggagct aatggattat acttactatg cagtatggcc cgatcctgat 3600 ttagttcatg atgatttttc tgtaatttgc caaggatttt atgaagatat agctcatgga 3660 aaagggaaag aactgaccaa agtcttctct gatggatcta cttgggtttc catgaagaac 3720 gtaagatttc tagatgactc tatacttaaa agaagagatg ttggttcagc agccttcaag 3780 atatttttga aatacctcaa gaagactggg tccaaaaacc tttgtgctgt tgaacttcct 3840 tcttcggtaa aattaggatt tgaagaagct ggctgcaaac agatactact tgaaaacaca 3900 ttttcagaga aacagttttt ttctgaagtg ttttttccaa atattcaaga aattgaagca 3960 gaacttagag atcctttaat gatctttgtt ctaaatgaaa aagttgatga gttctcggga 4020 gttcttcgtg ttactccatg tattccttgt tccttggagg ggcatccttt ggttttgcca 4080 tcaagattga tccaccccga aggacgagtt gcaaagttat ttgatattaa agatgggaga 4140 ttcccttatg gttctactca ggattatctc aatcctatta ttttgattaa actagttcag 4200 ttaggtatgg caaaagatga tattttatgg gatgatatgc tagaacgtgc agtgtcagta 4260 gctgaaatta ataaaagtga tcatgttgct gcatgcctaa gaagtagtat cttattgagt 4320 cttatcgatg agaaactaaa aataagggat cctagagcaa aggattttgc tgcaaaatat 4380 caaacaatcc gcttccttcc atttctgaca aaaccagcag gtttttcttt ggactggaaa 4440 ggcaacagtt ttaagcctga aaccatgttt gcagcaactg acctttatac agctgaacat 4500 caagatatag tttgtctttt gcaaccaatt ctaaatgaaa attcccattc ttttagaggt 4560 tgtggttcag tgtcattggc tgttaaagag tttttgggat tactcaagaa gccaacagtt 4620 gatctggtta taaaccaatt gaaagaagta gcaaaatcag ttgatgatgg aattacactg 4680 taccaggaga atatcaccaa tgcttgctac aaataccttc atgaagcctt gatgcaaaat 4740 gaaatcacta agatgtcaat tattgataag ttaaaaccct ttagcttcat tctagttgag 4800 aatgcatatg ttgactcaga aaaggtttct tttcatttaa attttgaggc ggcaccatac 4860 ctttatcagt tgcctaataa gtataaaaat aatttccgcg aactttttga aaccgtgggt 4920 gtgaggcagt catgcactgt tgaagatttt gctcttgttt tggaatctat tgatcaagaa 4980 agaggaacaa agcaaataac agaagagaat tttcagcttt gccgacgaat aatcagtgaa 5040 ggaatatgga gtctcattag agaaaagaaa caagaatttt gtgagaaaaa ttatggcaag 5100 atattattgc cagatactaa tcttatgctt ctccctgcta aatcgttatg ctacaatgat 5160 tgcccttgga taaaagtaaa ggataccact gtaaaatatt gtcatgctga catacccagg 5220 gaagtagcag taaaactagg agcagtccca aagtgacaca aagccttaga aagatatgca 5280 tccaatgtct gttttacaac acttggcaca gaatttgggc agaaagaaaa attgaccagc 5340 agaattaaga gcatccttaa tgcatatcct tctgaaaagg aaatgttgaa agagcttctt 5400 caaaatgctg atgatgcaaa ggcgacagaa atctgttttg tgtttgatcc tagacagcat 5460 ccagttgata gaatatttga tgataagtgg gccccattgc aagggccagc actttgtgtg 5520 tacaacaacc agccatttac agaagatgat gttagaggaa ttcagaatct tggaaaaggc 5580 acgaaagagg gaaatcctta taaaactgga cagtatggaa taggattcaa ttctgtgtat 5640 catatcacag actgcccatc ttttatttct ggcaatgaca tcctgtgtat ttttgatcct 5700 catgccagat atgcaccagg ggccacatcc attagtcccg gacgcatgtt tagagatttg 5760 gatgcagatt ttaggacaca gttctcagat gttctggatc tttatctggg aacccatttt 5820 aaactggata attgcacaat gttcagattt cctcttcgta atgcagaaat ggcaaaagtt 5880 tcggaaattt cgtctgttcc agcatcagac agaatggtcc agaatctttt ggacaaactg 5940 cgctcagatg gggcagaact tctaatgttt cttaatcaca tggaaaaaat ttctatttgt 6000 gaaatagata agagtactgg agctctaaat gtgctgtatt cagtaaaggg caaaatcaca 6060 gatggagaca gattgaaaag gaaacaattt catgcatctg taattgatag tgttactaaa 6120 aagaggcagc tcaaagacat accagttcaa caaataacct atactatgga tactgaggac 6180 tctgaaggaa atcttactac gtggctaatt tgtaatagat caggcttttc aagtatggag 6240 aaagtatcta aaagtgtcat atcagctcac aagaaccaag atattactct tttcccacgt 6300 ggtggagtag ctgcctgcat tactcacaac tataaaaaac cccatagggc cttctgtttt 6360 ttgcctcttt ctttggagac tgggctgcca tttcatgtga atggccactt tgcactggat 6420 tcagccagaa ggaacctgtg gcgtgatgat aatggagttg gtgttcgaag tgactggaat 6480 aacagtttaa tgacagcatt aatagctcct gcatatgttg aattgctaat acagttaaaa 6540 aaacggtatt tccctggttc tgatccaaca ttatcagtgt tacagaacac ccctattcat 6600 gttgtaaagg acactttaaa gaagttttta tcgtttttcc cagttaaccg tcttgatcta 6660 cagccagatt tatattgtct agtgaaagca ctttacaatt gcattcacga agacatgaaa 6720 cgtcttttac ctgttgtgcg ggctccaaat attgatggct ctgacttgca ctctgcagtt 6780 ataattactt ggatcaatat gtctacttct aataaaacta gaccattttt tgacaattta 6840 ctacaggatg aattacaaca ccttaaaaat gcagattata atatcaccac acgcaaaaca 6900 gtagcagaga atgtctatag gctgaaacat ctccttttag aaattggttt caacttggtt 6960 tataactgtg atgaaactgc taatctttac cactgtctta tagatgcaga tattcctgtt 7020 agttatgtga cccctgctga tatcagatct tttttaatga cattttcctc tcctgacact 7080 aattgccata ttgggaagct gccttgtcgt ctgcagcaga ctaatctaaa actttttcat 7140 agtttaaaac ttttagttga ttattgtttt aaagatgcag aagaaaatga gattgaagtt 7200 gagggattgc cccttctcat cacactggac agtgttttgc aaacttttga tgcaaaacga 7260 cccaagtttc taacaacata tcatgaattg attccatccc gcaaagactt gtttatgaat 7320 acattatatt tgaaatatag taatatttta ttgaactgta aagttgcaaa agtgtttgac 7380 atttccagct ttgctgattt gttatcctct gtgttgcctc gagaatataa gaccaaaagt 7440 tgcacaaagt ggaaagacaa ttttgcaagt gagtcttggc ttaagaatgc atggcatttt 7500 attagtgaat ctgtaagtgt gaaagaagat caggaagaaa caaaaccaac atttgacatt 7560 gttgttgata ctctaaaaga ctgggcattg cttccaggaa caaagtttac tgtttcagcc 7620 aaccagcttg tggttcctga aggagatgtt ctgcttcctc tcagccttat gcacattgca 7680 gtttttccaa atgcccagag tgataaagtt tttcatgctc taatgaaagc cggctgtatt 7740 cagcttgctt tgaacaaaat ctgttccaaa gacagtgcat ttgttccttt gttgtcatgt 7800 cacacagcaa atatagagag ccccacaagc atcttgaagg ctctacatta tatggtccaa 7860 acttcaacat ttagagcaga aaaattagta gaaaatgatt ttgaggcact tttgatgtat 7920 ttcaactgca atttgaatca tttgatgtcc caagatgata taaaaattct aaagtcactt 7980 ccgtgctata aatccatcag tggccgctat gtaagcattg gaaaatttgg aacatgctac 8040 gtacttacaa aaagtatccc ttcagctgaa gtggagaaat ggacacaatc atcatcatct 8100 gcatttcttg aagaaaaaat acacttaaaa gaactatatg aggtgattgg ttgtgtacct 8160 gtagatgatc ttgaggtata tttgaaacac ctcttaccaa aaattgaaaa tctctcttat 8220 gatgcaaaat tagagcactt gatctacctt aagaatagat tatcaagtgc tgaggaatta 8280 tcagagatta aggaacaact ttttgaaaaa ctggaaagtt tattgataat ccatgatgct 8340 aacagtagac taaagcaagc aaagcatttc tatgatagaa ctgtgagagt ttttgaagtt 8400 atgcttcctg aaaaattgtt tattcctaat gatttcttta agaaattgga acaacttata 8460 aaacccaaaa atcatgttac atttatgaca tcctgggtgg aattcttaag aaatattgga 8520 ctaaaataca tactttctca gcagcagttg ttacagtttg ctaaggaaat cagtgtgagg 8580 gctaatacag aaaactggtc caaagaaaca ttgcaaaata cagttgatat ccttctgcat 8640 catatattcc aagaacgaat ggatttgtta tctggaaatt ttctgaaaga actatcttta 8700 ataccattct tatgtcctga gcgggccccc gcggaattca ttagatttca tcctcaatat 8760 caagaggtaa atggaacact tcctcttata aagttcaatg gagcacaggt aaatccaaaa 8820 ttcaagcaat gtgatgtact ccagctgtta tggacatcct gccctattct tccagagaaa 8880 gctacaccct taagcattaa agaacaagaa ggtagtgacc ttggtccaca agaacagctt 8940 gaacaagttt taaatatgct taatgttaac ctggatcctc ctcttgataa ggtaatcaat 9000 aactgcagaa acatatgcaa cataacgacg ttggatgaag aaatggtaaa aactagagca 9060 aaagtcttaa ggagcatata tgaattcctc agtgcagaaa aaagggaatt tcgttttcag 9120 ttgcgagggg ttgcttttgt gatggtagaa gatggttgga aacttctgaa gcctgaggag 9180 gtagtcataa acctagaata tgaatctgat tttaaacctt atttgtacaa gctaccttta 9240 gaacttggca catttcacca gttgttcaaa cacttaggta ctgaagatat tatttcaact 9300 aagcaatatg ttgaagtgtt gagccgcata tttaaaaatt ctgagggcaa acaattagat 9360 cctaatgaaa tgcgtacagt taagagagta gtttctggtc tgttcaggag tctacagaat 9420 gattcagtca aggtgaggag tgatctcgag aatgtacgag accttgcgct ttacctccca 9480 agccaggatg gtagattggt aaagtcaagc atcttagtgt ttgacgatgc gccacattat 9540 aaaagtagaa tccaggggaa tattggtgtg caaatgttag ttgatctcag ccagtgctac 9600 ttagggaaag accatggatt tcacactaag ttgataatgc tctttcctca aaaacttaga 9660 cctcgattat tgagcagtat acttgaagaa caattagatg aagagactcc caaagtttgt 9720 cagtttggag cgttgtgttc tcttcaagga agattgcagt tactcttgtc ttctgaacag 9780 ttcattacag gactgattag aattatgaag catgaaaatg ataatgcttt tctggccaat 9840 gaagaaaaag ccataagact ttgcaaagcc ctaagagaag gattgaaagt atcctgcttt 9900 gaaaagcttc aaacaacatt aagagttaaa ggttttaatc ctattcccca cagcagaagt 9960 gaaacttttg cttttttgaa gcgatttggt aatgcagtca tcttgctcta cattcaacat 10020 tcagacagta aagacattaa tttcctgtta gcactggcaa tgactcttaa atcagcaact 10080 gacaatttga tttctgacac ttcatattta attgctatgc taggatgcaa tgatatttac 10140 aggattggtg agaaacttga cagtttagga gtgaaatatg actcttcgga gccatcaaaa 10200 ctggaacttc caatgcctgg cacaccaatt cctgctgaaa ttcattacac tctgcttatg 10260 gacccaatga atgtttttta cccgggagaa tatgttgggt accttgttga tgctgaaggt 10320 ggtgatatct atggatcata ccagccaaca tacacatatg caattattgt acaagaagtt 10380 gaaagagaag atgctgacaa ttctagtttt ctaggaaaga tatatcagat agatattggt 10440 tatagtgaat ataaaatagt tagctctctt gatctgtata agttttcaag acctgaggaa 10500 agctctcaaa gcagggacag tgctccttct acaccaacca gccccactga gttcctcacc 10560 cctggcctga gaagcattcc tcctcttttc tctggtagag agagccacaa gacttcttcc 10620 aaacatcagt cccccaaaaa gcttaaggtt aattctttac cagaaatctt aaaagaagtg 10680 acatctgtgg tggagcaagc atggaagctt ccagaatcgg aacgaaaaaa gattattagg 10740 cggttgtatt tgaaatggca tcctgacaaa aatccagaga accatgacat tgccaatgaa 10800 gtttttaaac atttgcagaa tgaaatcaac agattagaaa aacaggcttt tctagatcaa 10860 aatgcagaca gggcctccag acgaacattt tcaacctcag catcccgatt tcagtcagac 10920 aaatactcat ttcagagatt ctatacttca tggaatcaag aagcaacgag ccataaatct 10980 gaaagacagc aacagaacaa agaaaaatgc cccccttcag ccggacagac ttactctcaa 11040 aggttctttg ttcctcccac tttcaagtcg gttggcaatc cagtggaagc acgcagatgg 11100 ctaagacaag ccagagcaaa cttctcagct gccaggaatg accttcataa aaatgccaat 11160 gagtgggtgt gctttaaatg ttacctttct accaagttag ctttgattgc agctgactat 11220 gctgtgaggg gaaagtctga taaagatgta aaaccaactg cacttgctca gaaaatagag 11280 gaatatagtc agcaacttga aggactgaca aatgatgttc acacattgga agcttatggt 11340 gtagacagtt taaaaacaag ataccctgat ttgcttccct ttcctcagat cccaaatgac 11400 aggttcactt ctgaggttgc tatgagggtg atggaatgta ctgcctgtat cataataaaa 11460 cttgaaaatt ttatgcaaca aaaagtgtga agatatttaa cgaaaaaaaa ggtagatctt 11520 gaatgtgttg tagcacgaat aaattgctgt acttcattaa gcttcattgc caattagcta 11580 ggaattgtta agcacattgc agattgttct tggagaattc tggagttgtt atgaacatga 11640 ataccaacgg aaaaccttaa ctgaatctaa aagaaaacta ttttgaagat ggtggtgagc 11700 tgcaaaatag ctggatggat ttgaatgatt gggatgatac atcattgaac tgcactttat 11760 ataaccaaag cttagcagtt tgttagataa gagtctatgt atgtctctgg ttaggatgaa 11820 gttaatttta tgtttttaac atggtatttt tgaaggagct aatgaaacac tggacatata 11880 attggtttaa acataagggg aattaagtct ttgtagtctg tcattttttt aagtggatcc 11940 tcttggatgc gttattttct catcagctgg ctctgatcat gaatttgttg taattttatg 12000 ttgtactcag tgcatttaag aaatggtaga gtattttaat cctattactt gactaagagt 12060 gtgaaggtag tactttttag agtgcactga gtgcacttta catctttatt taaatttttt 12120 tttaacatct tatgtttaca ggcttcctgt ttgatgaaga tagcaacgga aaactcaaaa 12180 tggtggcagt tcttattacc agttgttagt attgtttctg gaaactgctt gccaagacaa 12240 catttattaa ctgttagaac acttgcttta tgtttgtgtg tacatatttt ccacaaatgt 12300 tataatttat atagtgtggt tgaacaggat gcaatctttt gttgtctaaa ggtgctgcag 12360 ttaaaaaaaa aacaaccttt tctttcaata tggcatgtag tggagttttt ttaactttaa 12420 aaacatcaaa aattgttaaa atcattgtgt tatctagtag tttataatta tcggcttata 12480 tttccccatg aatgatcaga actgacattt aattcatgtt tgtctcgcca tgcttcttta 12540 ctttaacata tttcttttgc agaatgtaaa aggtaatgat aattagttta tataagtgta 12600 ctggctgtaa atgatgctaa atatacttta tgcaattaag ggcttacaga acatgttgaa 12660 acttttttta cttttattgg gaataaggaa tgtttgcacc tccacatttt attgctt 12717 <210> SEQ ID NO 10 <211> LENGTH: 3559 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 10 Phe His Gly Leu Arg Trp Phe Gly Lys Ile Phe Ile Tyr Ile Phe Gln 1 5 10 15 Arg Ile Leu Tyr Leu Met Arg Cys His Leu Ser Pro Glu Leu Tyr Arg 20 25 30 Lys Val Arg His Val Trp Asn Ser Leu Asp Ser Gly Phe His Arg Ser 35 40 45 Phe Thr Met Asn Leu Lys His Ser Phe Gln Asn Phe Gln Thr Leu Tyr 50 55 60 Lys Asn Leu Glu Gly Leu Ser Leu Lys Asn Met His Leu Tyr Asn Ile 65 70 75 80 Arg Leu Leu Lys Asn Ile Phe Ile His His Tyr Gln Val Leu Phe Cys 85 90 95 Arg Trp Arg Arg Cys His Cys Arg Asn Cys Val Ile Lys Leu Arg Tyr 100 105 110 Phe Gln His Thr Lys Met Pro Gly Ser Ser Trp Leu Val Pro Ile Ala 115 120 125 Val Arg Lys Arg Lys Glu Leu Phe Lys Asn Trp Gln Tyr Ser Ser Ala 130 135 140 Leu Thr Ile Leu Leu Ile Arg Glu Phe Pro Leu Ile Gln Asn Lys Val 145 150 155 160 Val Lys Ser Tyr Thr Ile Leu Pro Asn Ser Gln Gln Ile Cys Asp Phe 165 170 175 Leu Phe Gln Thr Val Val Met Lys Leu Leu Phe Val Trp Gln Thr Cys 180 185 190 Lys Asn Ser Arg Pro Leu Ala Ala Ser Leu Phe Lys Ile Leu Lys Met 195 200 205 His Phe Ile His Met Lys Arg His Ser Leu Cys Tyr Gly Ser Leu Arg 210 215 220 Ile Tyr Leu Leu Leu Lys Met Arg Ile Gln Met Cys Leu Ser Gly His 225 230 235 240 His Asn Ser Ser Arg Tyr His Arg Asn Arg Trp Tyr Gln Leu Val Asn 245 250 255 Ser Leu Thr Leu Ile Lys Tyr Arg Ile Ser Phe Val Met Lys Lys Glu 260 265 270 Pro Ile Ser His Pro Gln Phe Leu Pro His Gln Ile Phe Phe Thr Pro 275 280 285 Asp Arg Leu Val Lys Thr Lys Pro Val Ser Lys Lys Arg Met Leu Cys 290 295 300 Lys Trp Gln Lys Lys Leu Lys Pro Tyr Arg Ser Val Leu Val Leu Ile 305 310 315 320 Lys Met Phe Phe Arg Lys Pro Lys Pro Ser Tyr Trp Phe Ile Arg Ile 325 330 335 Thr His Cys Cys Asn His Leu Lys Glu Arg His Arg Lys Asn Gly Phe 340 345 350 Gln Pro Ala Arg Lys Gly Leu Gln Ile Ile Gln Ala Leu Trp Ser Gly 355 360 365 Lys Glu Ile Ser Val Ile Ser Val His His Gln Ile Cys Val Met Ala 370 375 380 Met Gln Phe Ser Leu Ala Pro His Phe Leu Leu Leu Lys Val Ser Met 385 390 395 400 Thr Trp Lys Lys His Gly Ser Ser Gln Asn Leu Ala Leu Val Leu Ser 405 410 415 Asn Thr Leu Lys Leu Leu Leu Ile Gly Ile Leu Gln Lys Pro Leu Val 420 425 430 Met Lys Thr Thr Ile Asn Ser Ser Ile Phe Cys Leu Arg Phe Thr Asp 435 440 445 Ser Cys Met Ile Ile Met Lys Gly Lys Ile Leu Leu Glu Pro Asn Phe 450 455 460 His Gly Phe Gly Leu Ala Lys Ser Phe Val His Leu Pro Arg Leu Leu 465 470 475 480 Asn Gln Ser Met Ile Leu Thr Phe Ser Leu Ile Cys Ile Met Tyr Leu 485 490 495 Lys Pro Trp Gln Asn Ser Thr Asn Tyr Leu Arg Ser Val Val Gln Arg 500 505 510 Ser His Gln Ile Ile Phe Pro Trp Leu Phe Arg Arg Tyr Ile Ser Lys 515 520 525 Val Thr Lys Ile Ser Val Asn Lys Lys Ala Asn Lys Ile Phe Ile Leu 530 535 540 Cys Ile Leu Ser Asp Gly Cys Ile Ala Ile Arg Phe Gln Gln Ala Pro 545 550 555 560 Thr His Gln Phe Leu Tyr Ile Ile Ala Lys Ile Leu Leu Asn Leu Ser 565 570 575 Ser Gln Phe Thr Asn Ala Val Ile Val Thr Leu Lys Leu Met Thr Leu 580 585 590 Met Thr Tyr Leu Lys Ile Leu Trp Asn Gln Ser Phe Trp Cys Met Arg 595 600 605 Thr Tyr Pro Lys Leu Gln Asn Gly Lys Phe His Ala Leu Val Gln Asp 610 615 620 Ile Leu Lys Thr Trp Asp Leu Ser Ser Gln Asp Lys Glu Ser His Leu 625 630 635 640 Leu Glu Leu Lys Ile Phe Trp Lys Asn Thr Leu Gln Cys Gln Ile Phe 645 650 655 Leu Lys Asn Tyr Phe Lys Thr Leu Met Met Gln Met Gln Gln Asn Ala 660 665 670 Val Ser Leu Ile Glu Glu Ile Trp Thr Glu Arg Ile Ser Thr Gln Gly 675 680 685 Trp Gln Leu Val Met Asp Leu Leu Cys Gly His Ser Thr Ile Leu Asn 690 695 700 Ser Gln Ile Gln Ile Leu Thr Leu Gly Glu Asn Leu Lys Gly Glu Lys 705 710 715 720 Leu Thr Lys Leu Glu Asn Leu Val Leu Asp Leu Ile Leu Cys Thr Ile 725 730 735 Ser Leu Thr Phe Pro Ser Leu Val Gly Asn Ser Cys Ser Ile Gln Thr 740 745 750 Ile Ile Ser Val Asn Thr Leu Lys Thr Asn Pro Ile Leu Gly Ser Lys 755 760 765 Leu Ile Gly Val Asn Asn Arg Lys Asp Leu Glu Asn Phe Leu Ile Ser 770 775 780 Ser Asn His Leu Met Tyr Leu Ala Val Ser Tyr Leu Leu Lys His Leu 785 790 795 800 Thr Ala Ile Met Glu Pro Phe Ser Asp Cys Pro Leu Glu Leu Asn Arg 805 810 815 Lys Gln Lys Val Lys Leu Val Val Arg Ala Thr Ile Gln Gln Ile Phe 820 825 830 Ile Leu Leu Trp Met Asn Leu Val Ser Val Asp Thr Gly Leu Ser Phe 835 840 845 Ser Leu Arg Val Ser Gln Cys Ile Ser Thr Lys Leu Arg Lys Pro Thr 850 855 860 Pro Val His Lys Ile Gln Leu Lys Lys Asn Pro Ala Leu Pro Lys His 865 870 875 880 Thr His Leu Ser Val Phe Lys Arg Leu Leu Ser Ser Arg Leu Ala Ala 885 890 895 Ala Val Ile Lys Ser Phe Pro Val Met Asn Gln Ser His Leu Ala Phe 900 905 910 Phe Arg Ser Gln Trp Lys Asn Phe Thr Met Cys Ser Glu Gly Leu Leu 915 920 925 Ile Tyr Ser Arg His Phe Leu Glu Val Gln Met Met Thr Gln Leu Leu 930 935 940 Ser Leu Lys Trp Leu Ser Leu Ala Asn Gln Lys Ser His Gln Met Ser 945 950 955 960 Cys His Arg Lys Gln Ser Val Pro Arg Gly Phe Cys Val Leu Ala Trp 965 970 975 Thr Gln Glu Arg Leu Ser Phe Pro Val Arg Val Glu Glu Asp Asp Trp 980 985 990 Phe His Val Gly Gln Glu Phe Ser Cys Gln Lys Ser Arg Thr Arg Ser 995 1000 1005 Gly Gln Asn His Thr Leu Glu Arg Cys Phe Ala Ile Tyr Leu Tyr Glu 1010 1015 1020 Lys Gln Ala Cys Gln Phe Ile Ser Met Gly Ala Leu Leu Leu His Gln 1025 1030 1035 1040 Ile Gly Lys Lys Ser Gly Lys Gln Ile Gln Lys Asp Asp Gly Ile Pro 1045 1050 1055 Arg Ser Asp Met Leu Leu Lys Leu Thr Tyr Arg Tyr Val Ser Tyr Gly 1060 1065 1070 Thr Trp Pro Leu Val Gly Ser Trp Ile Ile Leu Thr Met Gln Tyr Gly 1075 1080 1085 Pro Ile Leu Ile Phe Met Met Ile Phe Leu Phe Ala Lys Asp Phe Met 1090 1095 1100 Lys Ile Leu Met Glu Lys Gly Lys Asn Pro Lys Ser Ser Leu Met Asp 1105 1110 1115 1120 Leu Leu Gly Phe Pro Arg Thr Asp Phe Met Thr Leu Tyr Leu Lys Glu 1125 1130 1135 Glu Met Leu Val Gln Gln Pro Ser Arg Tyr Phe Asn Thr Ser Arg Arg 1140 1145 1150 Leu Gly Pro Lys Thr Phe Val Leu Leu Asn Phe Leu Leu Arg Asn Asp 1155 1160 1165 Leu Lys Lys Leu Ala Ala Asn Arg Tyr Tyr Leu Lys Thr His Phe Gln 1170 1175 1180 Arg Asn Ser Phe Phe Leu Lys Cys Phe Phe Gln Ile Phe Lys Lys Leu 1185 1190 1195 1200 Lys Gln Asn Leu Glu Ile Leu Ser Leu Phe Met Lys Lys Leu Met Ser 1205 1210 1215 Ser Arg Glu Phe Phe Val Leu Leu His Val Phe Leu Val Pro Trp Arg 1220 1225 1230 Gly Ile Leu Trp Phe Cys His Gln Asp Ser Thr Pro Lys Asp Glu Leu 1235 1240 1245 Gln Ser Tyr Leu Ile Leu Lys Met Gly Asp Ser Leu Met Val Leu Leu 1250 1255 1260 Arg Ile Ile Ser Ile Leu Leu Phe Leu Asn Phe Ser Val Trp Gln Lys 1265 1270 1275 1280 Met Ile Phe Tyr Gly Met Ile Cys Asn Val Gln Cys Gln Leu Lys Leu 1285 1290 1295 Ile Lys Val Ile Met Leu Leu His Ala Glu Val Val Ser Tyr Val Leu 1300 1305 1310 Ser Met Arg Asn Lys Gly Ile Leu Glu Gln Arg Ile Leu Leu Gln Asn 1315 1320 1325 Ile Lys Gln Ser Ala Ser Phe His Phe Gln Asn Gln Gln Val Phe Leu 1330 1335 1340 Trp Thr Gly Lys Ala Thr Val Leu Ser Leu Lys Pro Cys Leu Gln Gln 1345 1350 1355 1360 Leu Thr Phe Ile Gln Leu Asn Ile Lys Ile Phe Val Phe Cys Asn Gln 1365 1370 1375 Phe Met Lys Ile Pro Ile Leu Leu Glu Val Val Val Gln Cys His Trp 1380 1385 1390 Leu Leu Lys Ser Phe Trp Asp Tyr Ser Arg Ser Gln Gln Leu Ile Trp 1395 1400 1405 Leu Thr Asn Lys Lys Gln Asn Gln Leu Met Met Glu Leu His Cys Thr 1410 1415 1420 Arg Arg Ile Ser Pro Met Leu Ala Thr Asn Thr Phe Met Lys Pro Cys 1425 1430 1435 1440 Lys Met Lys Ser Leu Arg Cys Gln Leu Leu Ile Ser Asn Pro Leu Ala 1445 1450 1455 Ser Phe Leu Arg Met His Met Leu Thr Gln Lys Arg Phe Leu Phe Ile 1460 1465 1470 Ile Leu Arg Arg His His Thr Phe Ile Ser Cys Leu Ile Ser Ile Lys 1475 1480 1485 Ile Ile Ser Ala Asn Phe Leu Lys Pro Trp Val Gly Ser His Ala Leu 1490 1495 1500 Leu Lys Ile Leu Leu Leu Phe Trp Asn Leu Leu Ile Lys Lys Glu Glu 1505 1510 1515 1520 Gln Ser Lys Gln Lys Arg Ile Phe Ser Phe Ala Asp Glu Ser Val Lys 1525 1530 1535 Glu Tyr Gly Val Ser Leu Glu Lys Arg Asn Lys Asn Phe Val Arg Lys 1540 1545 1550 Ile Met Ala Arg Tyr Tyr Cys Gln Ile Leu Ile Leu Cys Phe Ser Leu 1555 1560 1565 Leu Asn Arg Tyr Ala Thr Met Ile Ala Leu Gly Lys Arg Ile Pro Leu 1570 1575 1580 Asn Ile Val Met Leu Thr Tyr Pro Gly Lys Gln Asn Glu Gln Ser Gln 1585 1590 1595 1600 Ser Asp Thr Lys Pro Lys Asp Met His Pro Met Ser Val Leu Gln His 1605 1610 1615 Leu Ala Gln Asn Leu Gly Arg Lys Lys Asn Pro Ala Glu Leu Arg Ala 1620 1625 1630 Ser Leu Met His Ile Leu Leu Lys Arg Lys Cys Lys Ser Phe Phe Lys 1635 1640 1645 Met Leu Met Met Gln Arg Arg Gln Lys Ser Val Leu Cys Leu Ile Leu 1650 1655 1660 Asp Ser Ile Gln Leu Ile Glu Tyr Leu Met Ile Ser Gly Pro His Cys 1665 1670 1675 1680 Lys Gly Gln His Phe Val Cys Thr Thr Thr Ser His Leu Gln Lys Met 1685 1690 1695 Met Leu Glu Glu Phe Arg Ile Leu Glu Lys Ala Arg Lys Arg Glu Ile 1700 1705 1710 Leu Ile Lys Leu Asp Ser Met Glu Asp Ser Ile Leu Cys Ile Ile Ser 1715 1720 1725 Gln Thr Ala His Leu Leu Phe Leu Ala Met Thr Ser Cys Val Phe Leu 1730 1735 1740 Ile Leu Met Pro Asp Met His Gln Gly Pro His Pro Leu Val Pro Asp 1745 1750 1755 1760 Ala Cys Leu Glu Ile Trp Met Gln Ile Leu Gly His Ser Ser Gln Met 1765 1770 1775 Phe Trp Ile Phe Ile Trp Glu Pro Ile Leu Asn Trp Ile Ile Ala Gln 1780 1785 1790 Cys Ser Asp Phe Leu Phe Val Met Gln Lys Trp Gln Lys Phe Arg Lys 1795 1800 1805 Phe Arg Leu Phe Gln His Gln Thr Glu Trp Ser Arg Ile Phe Trp Thr 1810 1815 1820 Asn Cys Ala Gln Met Gly Gln Asn Phe Cys Phe Leu Ile Thr Trp Lys 1825 1830 1835 1840 Lys Phe Leu Phe Val Lys Ile Arg Val Leu Glu Leu Met Cys Cys Ile 1845 1850 1855 Gln Arg Ala Lys Ser Gln Met Glu Thr Asp Lys Gly Asn Asn Phe Met 1860 1865 1870 His Leu Leu Ile Val Leu Leu Lys Arg Gly Ser Ser Lys Thr Tyr Gln 1875 1880 1885 Phe Asn Lys Pro Ile Leu Trp Ile Leu Arg Thr Leu Lys Glu Ile Leu 1890 1895 1900 Leu Arg Gly Phe Val Ile Asp Gln Ala Phe Gln Val Trp Arg Lys Tyr 1905 1910 1915 1920 Leu Lys Val Ser Tyr Gln Leu Thr Arg Thr Lys Ile Leu Leu Phe Ser 1925 1930 1935 His Val Val Glu Leu Pro Ala Leu Leu Thr Thr Ile Lys Asn Pro Ile 1940 1945 1950 Gly Pro Ser Val Phe Cys Leu Phe Leu Trp Arg Leu Gly Cys His Phe 1955 1960 1965 Met Met Ala Thr Leu His Trp Ile Gln Pro Glu Gly Thr Cys Gly Val 1970 1975 1980 Met Ile Met Glu Leu Val Phe Glu Val Thr Gly Ile Thr Val Gln His 1985 1990 1995 2000 Leu Leu His Met Leu Asn Cys Tyr Ser Lys Asn Gly Ile Ser Leu Val 2005 2010 2015 Leu Ile Gln His Tyr Gln Cys Tyr Arg Thr Pro Leu Phe Met Leu Arg 2020 2025 2030 Thr Leu Arg Ser Phe Tyr Arg Phe Ser Gln Leu Thr Val Leu Ile Tyr 2035 2040 2045 Ser Gln Ile Tyr Ile Val Lys His Phe Thr Ile Ala Phe Thr Lys Thr 2050 2055 2060 Asn Val Phe Tyr Leu Leu Cys Gly Leu Gln Ile Leu Met Ala Leu Thr 2065 2070 2075 2080 Cys Thr Leu Gln Leu Leu Leu Gly Ser Ile Cys Leu Leu Leu Ile Lys 2085 2090 2095 Leu Asp His Phe Leu Thr Ile Tyr Tyr Arg Met Asn Tyr Asn Thr Leu 2100 2105 2110 Lys Met Gln Ile Ile Ile Ser Pro His Ala Lys Gln Gln Arg Met Ser 2115 2120 2125 Ile Gly Asn Ile Ser Phe Lys Leu Val Ser Thr Trp Phe Ile Thr Val 2130 2135 2140 Met Lys Leu Leu Ile Phe Thr Thr Val Leu Met Gln Ile Phe Leu Leu 2145 2150 2155 2160 Val Met Pro Leu Leu Ile Ser Asp Leu Phe His Phe Pro Leu Leu Thr 2165 2170 2175 Leu Ile Ala Ile Leu Gly Ser Cys Leu Val Val Cys Ser Arg Leu Ile 2180 2185 2190 Asn Phe Phe Ile Val Asn Phe Leu Ile Ile Val Leu Lys Met Gln Lys 2195 2200 2205 Lys Met Arg Leu Lys Leu Arg Asp Cys Pro Phe Ser Ser His Trp Thr 2210 2215 2220 Val Phe Cys Lys Leu Leu Met Gln Asn Asp Pro Ser Phe Gln His Ile 2225 2230 2235 2240 Met Asn Phe His Pro Ala Lys Thr Cys Leu Ile His Tyr Ile Asn Ile 2245 2250 2255 Val Ile Phe Tyr Thr Val Lys Leu Gln Lys Cys Leu Thr Phe Pro Ala 2260 2265 2270 Leu Leu Ile Cys Tyr Pro Leu Cys Cys Leu Glu Asn Ile Arg Pro Lys 2275 2280 2285 Val Ala Gln Ser Gly Lys Thr Ile Leu Gln Val Ser Leu Gly Leu Arg 2290 2295 2300 Met His Gly Ile Leu Leu Val Asn Leu Val Lys Lys Ile Arg Lys Lys 2305 2310 2315 2320 Gln Asn Gln His Leu Thr Leu Leu Leu Ile Leu Lys Thr Gly His Cys 2325 2330 2335 Phe Gln Glu Gln Ser Leu Leu Phe Gln Pro Thr Ser Leu Trp Phe Leu 2340 2345 2350 Lys Glu Met Phe Cys Phe Leu Ser Ala Leu Cys Thr Leu Gln Phe Phe 2355 2360 2365 Gln Met Pro Arg Val Ile Lys Phe Phe Met Leu Lys Pro Ala Val Phe 2370 2375 2380 Ser Leu Leu Thr Lys Ser Val Pro Lys Thr Val His Leu Phe Leu Cys 2385 2390 2395 2400 Cys His Val Thr Gln Gln Ile Arg Ala Pro Gln Ala Ser Arg Leu Tyr 2405 2410 2415 Ile Ile Trp Ser Lys Leu Gln His Leu Glu Gln Lys Asn Lys Met Ile 2420 2425 2430 Leu Arg His Phe Cys Ile Ser Thr Ala Ile Ile Ile Cys Pro Lys Met 2435 2440 2445 Ile Lys Phe Ser His Phe Arg Ala Ile Asn Pro Ser Val Ala Ala Met 2450 2455 2460 Ala Leu Glu Asn Leu Glu His Ala Thr Tyr Leu Gln Lys Val Ser Leu 2465 2470 2475 2480 Gln Leu Lys Trp Arg Asn Gly His Asn His His His Leu His Phe Leu 2485 2490 2495 Lys Lys Lys Tyr Thr Lys Asn Tyr Met Arg Leu Val Val Tyr Leu Met 2500 2505 2510 Ile Leu Arg Tyr Ile Asn Thr Ser Tyr Gln Lys Leu Lys Ile Ser Leu 2515 2520 2525 Met Met Gln Asn Ser Thr Ser Thr Leu Arg Ile Asp Tyr Gln Val Leu 2530 2535 2540 Arg Asn Tyr Gln Arg Leu Arg Asn Asn Phe Leu Lys Asn Trp Lys Val 2545 2550 2555 2560 Tyr Ser Met Met Leu Thr Val Asp Ser Lys Gln Ser Ile Ser Met Ile 2565 2570 2575 Glu Leu Glu Phe Leu Lys Leu Cys Phe Leu Lys Asn Cys Leu Phe Leu 2580 2585 2590 Met Ile Ser Leu Arg Asn Trp Asn Asn Leu Asn Pro Lys Ile Met Leu 2595 2600 2605 His Leu His Pro Gly Trp Asn Ser Glu Ile Leu Asp Asn Thr Tyr Phe 2610 2615 2620 Leu Ser Ser Ser Cys Tyr Ser Leu Leu Arg Lys Ser Val Gly Leu Ile 2625 2630 2635 2640 Gln Lys Thr Gly Pro Lys Lys His Cys Lys Ile Gln Leu Ile Ser Phe 2645 2650 2655 Cys Ile Ile Tyr Ser Lys Asn Glu Trp Ile Cys Tyr Leu Glu Ile Phe 2660 2665 2670 Lys Asn Tyr Leu Tyr His Ser Tyr Val Leu Ser Gly Pro Pro Arg Asn 2675 2680 2685 Ser Leu Asp Phe Ile Leu Asn Ile Lys Arg Met Glu His Phe Leu Leu 2690 2695 2700 Ser Ser Met Glu His Arg Ile Gln Asn Ser Ser Asn Val Met Tyr Ser 2705 2710 2715 2720 Ser Cys Tyr Gly His Pro Ala Leu Phe Phe Gln Arg Lys Leu His Pro 2725 2730 2735 Ala Leu Lys Asn Lys Lys Val Val Thr Leu Val His Lys Asn Ser Leu 2740 2745 2750 Asn Lys Phe Ile Cys Leu Met Leu Thr Trp Ile Leu Leu Leu Ile Arg 2755 2760 2765 Ser Ile Thr Ala Glu Thr Tyr Ala Thr Arg Arg Trp Met Lys Lys Trp 2770 2775 2780 Lys Leu Glu Gln Lys Ser Gly Ala Tyr Met Asn Ser Ser Val Gln Lys 2785 2790 2795 2800 Lys Gly Asn Phe Val Phe Ser Cys Glu Gly Leu Leu Leu Trp Lys Met 2805 2810 2815 Val Gly Asn Phe Ser Leu Arg Arg Ser Thr Asn Met Asn Leu Ile Leu 2820 2825 2830 Asn Leu Ile Cys Thr Ser Tyr Leu Asn Leu Ala His Phe Thr Ser Cys 2835 2840 2845 Ser Asn Thr Val Leu Lys Ile Leu Phe Gln Leu Ser Asn Met Leu Lys 2850 2855 2860 Cys Ala Ala Tyr Leu Lys Ile Leu Arg Ala Asn Asn Ile Leu Met Lys 2865 2870 2875 2880 Cys Val Gln Leu Arg Glu Phe Leu Val Cys Ser Gly Val Tyr Arg Met 2885 2890 2895 Ile Gln Ser Arg Gly Val Ile Ser Arg Met Tyr Glu Thr Leu Arg Phe 2900 2905 2910 Thr Ser Gln Ala Arg Met Val Asp Trp Ser Gln Ala Ser Cys Leu Thr 2915 2920 2925 Met Arg His Ile Ile Lys Val Glu Ser Arg Gly Ile Leu Val Cys Lys 2930 2935 2940 Cys Leu Ile Ser Ala Ser Ala Thr Gly Lys Thr Met Asp Phe Thr Leu 2945 2950 2955 2960 Ser Cys Ser Phe Leu Lys Asn Leu Asp Leu Asp Tyr Ala Val Tyr Leu 2965 2970 2975 Lys Asn Asn Met Lys Arg Leu Pro Lys Phe Val Ser Leu Glu Arg Cys 2980 2985 2990 Val Leu Phe Lys Glu Asp Cys Ser Tyr Ser Cys Leu Leu Asn Ser Ser 2995 3000 3005 Leu Gln Asp Leu Glu Leu Ser Met Lys Met Ile Met Leu Phe Trp Pro 3010 3015 3020 Met Lys Lys Lys Pro Asp Phe Ala Lys Pro Glu Lys Asp Lys Tyr Pro 3025 3030 3035 3040 Ala Leu Lys Ser Phe Lys Gln His Glu Leu Lys Val Leu Ile Leu Phe 3045 3050 3055 Pro Thr Ala Glu Val Lys Leu Leu Leu Phe Ser Asp Leu Val Met Gln 3060 3065 3070 Ser Ser Cys Ser Thr Phe Asn Ile Gln Thr Val Lys Thr Leu Ile Ser 3075 3080 3085 Cys His Trp Gln Leu Leu Asn Gln Gln Leu Thr Ile Phe Leu Thr Leu 3090 3095 3100 His Ile Leu Leu Cys Asp Ala Met Ile Phe Thr Gly Leu Val Arg Asn 3105 3110 3115 3120 Leu Thr Val Glu Asn Met Thr Leu Arg Ser His Gln Asn Trp Asn Phe 3125 3130 3135 Gln Cys Leu Ala His Gln Phe Leu Leu Lys Phe Ile Thr Leu Cys Leu 3140 3145 3150 Trp Thr Gln Met Phe Phe Thr Arg Glu Asn Met Leu Gly Thr Leu Leu 3155 3160 3165 Met Leu Lys Val Val Ile Ser Met Asp His Thr Ser Gln His Thr His 3170 3175 3180 Met Gln Leu Leu Tyr Lys Lys Leu Lys Glu Lys Met Leu Thr Ile Leu 3185 3190 3195 3200 Val Phe Glu Arg Tyr Ile Arg Ile Leu Val Ile Val Asn Ile Lys Leu 3205 3210 3215 Ala Leu Leu Ile Cys Ile Ser Phe Gln Asp Leu Arg Lys Ala Leu Lys 3220 3225 3230 Ala Gly Thr Val Leu Leu Leu His Gln Pro Ala Pro Leu Ser Ser Ser 3235 3240 3245 Pro Leu Ala Glu Ala Phe Leu Leu Phe Ser Leu Val Glu Arg Ala Thr 3250 3255 3260 Arg Leu Leu Pro Asn Ile Ser Pro Pro Lys Ser Leu Arg Leu Ile Leu 3265 3270 3275 3280 Tyr Gln Lys Ser Lys Lys His Leu Trp Trp Ser Lys His Gly Ser Phe 3285 3290 3295 Gln Asn Arg Asn Glu Lys Arg Leu Leu Gly Gly Cys Ile Asn Gly Ile 3300 3305 3310 Leu Thr Lys Ile Gln Arg Thr Met Thr Leu Pro Met Lys Phe Leu Asn 3315 3320 3325 Ile Cys Arg Met Lys Ser Thr Asp Lys Asn Arg Leu Phe Ile Lys Met 3330 3335 3340 Gln Thr Gly Pro Pro Asp Glu His Phe Gln Pro Gln His Pro Asp Phe 3345 3350 3355 3360 Ser Gln Thr Asn Thr His Phe Arg Asp Ser Ile Leu His Gly Ile Lys 3365 3370 3375 Lys Gln Arg Ala Ile Asn Leu Lys Asp Ser Asn Arg Thr Lys Lys Asn 3380 3385 3390 Ala Pro Leu Gln Pro Asp Arg Leu Thr Leu Lys Gly Ser Leu Phe Leu 3395 3400 3405 Pro Leu Ser Ser Arg Leu Ala Ile Gln Trp Lys His Ala Asp Gly Asp 3410 3415 3420 Lys Pro Glu Gln Thr Ser Gln Leu Pro Gly Met Thr Phe Ile Lys Met 3425 3430 3435 3440 Pro Met Ser Gly Cys Ala Leu Asn Val Thr Phe Leu Pro Ser Leu Leu 3445 3450 3455 Gln Leu Thr Met Leu Gly Glu Ser Leu Ile Lys Met Asn Gln Leu His 3460 3465 3470 Leu Leu Arg Lys Arg Asn Ile Val Ser Asn Leu Lys Asp Gln Met Met 3475 3480 3485 Phe Thr His Trp Lys Leu Met Val Thr Val Lys Gln Asp Thr Leu Ile 3490 3495 3500 Cys Phe Pro Phe Leu Arg Ser Gln Met Thr Gly Ser Leu Leu Arg Leu 3505 3510 3515 3520 Leu Gly Trp Asn Val Leu Pro Val Ser Asn Leu Lys Ile Leu Cys Asn 3525 3530 3535 Lys Lys Cys Glu Asp Ile Arg Lys Lys Arg Ile Leu Asn Val Leu His 3540 3545 3550 Glu Ile Ala Val Leu His Ala 3555 <210> SEQ ID NO 11 <211> LENGTH: 12793 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 11 atgatttaca ggaagaccat gtactcagct gcagcttcta aatccagaac gatttgcacg 60 tcttatcaag gaagtaatga atacattctg gcctggcaga gaattgattg ttcaatggta 120 tccatttgat gaaaacagaa atcacccatc tgtttcatgg cttaagatgg tttggaaaaa 180 tctttatata catttttcag aggatttgac tttatttgat gagatgccac ttatccccag 240 aactatacta gaggaaggtc agacatgtgt ggaactcatt agactcagga ttccatcgtt 300 agtcatttta gacgatgaat ctgaagcaca gcttccagaa tttttagcag acattgtaca 360 aaaacttgga gggtttgtcc ttaaaaaatt agatgcatct atacaacatc cgcttattaa 420 aaaatatatt cattcaccat taccaagtgc tgttttgcag ataatggaga agatgccatt 480 gcagaaattg tgtaatcaaa taacttcgct acttccaaca cacaaagatg ccctgaggaa 540 gttcttggct agtttaaccg atagcagtga gaaagagaaa agaattattc aagaattggc 600 aatattcaag cgcattaacc attcttctga tcagggaatt tcctcttata caaaattgaa 660 aggttgtaaa gtcttacacc atactgccaa actcccagca gatctgcgac tttctatttc 720 agtaatagac agtagtgatg aagctactat tcgtctggca aacatgttga aaatagaaca 780 gttaaagacc actagctgct taaagcttgt tttaaaagat attgaaaatg cattttattc 840 acatgaagag gtaacacagc ttatgttatg ggtccttgag aatctatctt ctcttaaaaa 900 tgagaatcca aatgtgcttg agtggttaac accattaaaa ttcatccaga tatcacagga 960 acagatggta tcagctggtg aactctttga ccctgatata gaagtactaa aggatctctt 1020 ttgtaatgaa gaaggaacct atttcccacc ctcagttttt acctcaccag atattcttca 1080 ctccttaaga cagattggtt taaaaaacga agccagtctc aaagaaaagg atgttgtgca 1140 agtggcaaaa aaaattgaag ccttacaggt cggtgcttgt cctgatcaag atgttcttct 1200 gaagaaagcc aaaaccctct tactggtttt aaataagaat cacacactgt tgcaatcatc 1260 tgaaggaaag atgacattga agaaaataaa atgggttcca gcctgcaagg aaaggcctcc 1320 aaattatcca ggctctttgg tctggaaagg agatctctgt aatctctgtg caccaccaga 1380 tatgtgtgat gtaggccatg caattctcat tggctcctca cttcctcttg ttgaaagtat 1440 ccatgtaaac ctggaaaaag cattagggat cttcacaaaa cctagcctta gtgctgtctt 1500 aaaacacttt aaaattgttg ttgattggta ttcttcaaaa acctttagtg atgaagacta 1560 ctatcaattc cagcatattt tgcttgagat ttacggattc atgcatgatc atctaaatga 1620 agggaaagat tcttttagag ccttaaaatt tccatgggtt tggactggca aaaagttttg 1680 tccacttgcc caggctgtga ttaaaccaat ccatgatctt gaccttcagc cttatttgca 1740 taatgtacct aaaaccatgg caaaattcca ccaactattt aaggtctgtg gttcaataga 1800 ggagttgaca tcagatcata tttccatggt tattcagaag atatatctca aaagtgacca 1860 agatctcagt gaacaagaaa gcaaacaaaa tcttcatctt atgttgaata ttatcagatg 1920 gctgtatagc aatcagattc cagcaagccc caacacacca gttcctatac atcatagcaa 1980 aaatccttct aaacttatca tgaagccaat tcacgaatgc tgttattgtg acattaaagt 2040 tgatgacctt aatgacttac ttgaagattc tgtggaacca atcattttgg tgcatgagga 2100 catacccatg aaaactgcag aatggctaaa agttccatgc cttagtacaa gactgataaa 2160 tcctgaaaac atgggatttg agcagtcagg acaaagagag ccacttactg taagaattaa 2220 aaatattctg gaagaatacc cttcagtgtc agatattttt aaagaactac ttcaaaacgc 2280 tgatgatgca aatgcaacag aatgcagttt cttgattgat atgagaagaa atatggacat 2340 aagagagaat ctcctagacc cagggatggc agcttgtcat ggacctgctt tgtggtcatt 2400 caacaattct caattctcag attcagattt tgtgaacata actaggttag gagaatcttt 2460 aaaaagggga gaagttgaca aagttggaaa atttggtctt ggatttaatt ctgtgtacca 2520 tatcactgac attcccatca ttatgagtcg ggaattcatg ataatgttcg atccaaacat 2580 aaatcatatc agtaaacaca ttaaagacaa atccaatcct gggatcaaaa ttaattggag 2640 taaacaacag aaaagactta gaaaatttcc taatcagttc aaaccattta tagatgtatt 2700 tggctgtcag ttacctttga ctgtagaagc accttacagc tataatggaa cccttttccg 2760 actgtccttt agaactcaac aggaagcaaa agtgagtgaa gttagtagta cgtgctacaa 2820 tacagcagat atttattctc ttgtggatga atttagtctc tgtggacaca ggcttatcat 2880 tttcactcag agtgtaaagt caatgtattt gaagtacttg aaaattgagg aaaccaaccc 2940 cagtttagca caagatacag taataattaa aaaaaaatcc tgctcttcca aagcattgaa 3000 cacacctgtc ttaagtgttt taaaagaggc tgctaagctc atgaagactt gcagcagcag 3060 taataaaaag cttcccagtg atgaaccaaa gtcatcttgc attcttcaga tcacagtgga 3120 agaatttcac catgtgttca gaaggattgc tgatttacag tcgccacttt ttagaggtcc 3180 agatgatgac ccagctgctc tctttgaaat ggctaagtct ggccaatcaa aaaagccatc 3240 agatgagttg tcacagaaaa cagtagagtg taccacgtgg cttctgtgta cttgcatgga 3300 cacaggagag gctctgaagt tttccctgag tgagagtgga agaagactag gactggttcc 3360 atgtggggca gtaggagttc agctgtcaga aatccaggac cagaagtgga cagtgaaacc 3420 acacattgga gaggtgtttt gctatttacc tttacgaata aaaacaggct tgccagttca 3480 tatcaatggg tgctttgctg ttacatcaaa taggaaagaa atctggaaaa cagatacaaa 3540 aggacgatgg aataccacgt tcatgagaca tgttattgtg aaagcttact tacaggtact 3600 gagtgtctta cgggacctgg ccactagtgg ggagctaatg gattatactt actatgcagt 3660 atggcccgat cctgatttag ttcatgatga tttttctgta atttgccaag gattttatga 3720 agatatagct catggaaaag ggaaagaact gaccaaagtc ttctctgatg gatctacttg 3780 ggtttccatg aagaacgtaa gatttctaga tgactctata cttaaaagaa gagatgttgg 3840 ttcagcagcc ttcaagatat ttttgaaata cctcaagaag actgggtcca aaaacctttg 3900 tgctgttgaa cttccttctt cggtaaaatt aggatttgaa gaagttggct gcaaacagat 3960 actacttgaa aacacatttt cagagaaaca gtttttttct gaagtgtttt ttccaaatat 4020 tcaagaaatt gaagcagaac ttagagatcc tttaatgatc tttgttctaa atgaaaaagt 4080 tgatgagttc tcgggagttc ttcgtgttac tccatgtatt ccttgttcct tggaggggca 4140 tcctttggtt ttgccatcaa gattgatcca ccccgaagga cgagttgcaa agttatttga 4200 tattaaagat gggagattcc cttatggttc tactcaggat tatctcaatc ctattatttt 4260 gattaaacta gttcagttag gtatggcaaa agatgatatt ttatgggatg atatgctaga 4320 acgtgcagtg tcagtagctg aaattaataa aagtgatcat gttgctgcat gcctaagaag 4380 tagtatctta ttgagtctta tcgatgagaa actaaaaata agggatccta gagcaaagga 4440 ttttgctgca aaatatcaaa caatccgctt ccttccattt ctgacaaaac cagcaggttt 4500 ttctttggac tggaaaggca acagttttaa gcctgaaacc atgtttgcag caactgacct 4560 ttatacagct gaacatcaag atatagtttg tcttttgcaa ccaattctaa atgaaaattc 4620 ccattctttt agaggttgtg gttcagtgtc attggctgtt aaagagtttt tgggattact 4680 caagaagcca acagttgatc tggttataaa ccaattgaaa gaagtagcaa aatcagttga 4740 tgatggaatt acactgtacc aggagaatat caccaatgct tgctacaaat accttcatga 4800 agccttgatg caaaatgaaa tcactaagat gtcaattatt gataagttaa aaccctttag 4860 cttcattcta gttgagaatg catatgttga ctcagaaaag gtttcttttc atttaaattt 4920 tgaggcggca ccataccttt atcagttgcc taataagtat aaaaataatt tccgcgaact 4980 ttttgaaacc gtgggtgtga ggcagtcatg cactgttgaa gattttgctc ttgttttgga 5040 atctattgat caagaaagag gaacaaagca aataacagaa gagaattttc agctttgccg 5100 acgaataatc agtgaaggaa tatggagtct cattagagaa aagaaacaag aattttgtga 5160 gaaaaattat ggcaagatat tattgccaga tactaatctt atgcttctcc ctgctaaatc 5220 gttatgctac aatgattgcc cttggataaa agtaaaggat accactgtaa aatattgtca 5280 tgctgacata cccagggaag tagcagtaaa actaggagca gtcccaaagc gacacaaagc 5340 cttagaaaga tatgcatcca atgtctgttt tacaacactt ggcacagaat ttgggcagaa 5400 agaaaaattg accagcagaa ttaagagcat ccttaatgca tatccttctg aaaaggaaat 5460 gttgaaagag cttcttcaaa atgctgatga tgcaaaggcg acagaaatct gttttgtgtt 5520 tgatcctaga cagcatccag ttgatagaat atttgatgat aagtgggccc cattgcaagg 5580 gccagcactt tgtgtgtaca acaaccagcc atttacagaa gatgatgtta gaggaattca 5640 gaatcttgga aaaggcacga aagagggaaa tccttataaa actggacagt atggaatagg 5700 attcaattct gtgtatcata tcacagactg cccatctttt atttctggca atgacatcct 5760 gtgtattttt gatcctcatg ccagatatgc accaggggcc acatccatta gtcccggacg 5820 catgtttaga gatttggatg cagattttag gacacagttc tcagatgttc tggatcttta 5880 tctgggaacc cattttaaac tggataattg cacaatgttc agatttcctc ttcgtaatgc 5940 agaaatggca aaagtttcgg aaatttcgtc tgttccagca tcagacagaa tggtccagaa 6000 tcttttggac aaactgcgct cagatggggc agaacttcta atgtttctta atcacatgga 6060 aaaaatttct atttgtgaaa tagataagag tactggagct ctaaatgtgc tgtattcagt 6120 aaagggcaaa atcacagatg gagacagatt gaaaaggaaa caatttcatg catctgtaat 6180 tgatagtgtt actaaaaaga ggcagctcaa agacatacca gttcaacaaa taacctatac 6240 tatggatact gaggactctg aaggaaatct tactacgtgg ctaatttgta atagatcagg 6300 cttttcaagt atggagaaag tatctaaaag tgtcatatca gctcacaaga accaagatat 6360 tactcttttc ccacgtggtg gagtagctgc ctgcattact cacaactata aaaaacccca 6420 tagggccttc tgttttttgc ctctttcttt ggagactggg ctgccatttc atgtgaatgg 6480 ccactttgca ctggattcag ccagaaggaa cctgtggcgt gatgataatg gagttggtgt 6540 tcgaagtgac tggaataaca gtttaatgac agcattaata gctcctgcat atgttgaatt 6600 gctaatacag ttaaaaaaac ggtatttccc tggttctgat ccaacattat cagtgttaca 6660 gaacacccct attcatgttg taaaggacac tttaaagaag tttttatcgt ttttcccagt 6720 taaccgtctt gatctacagc cagatttata ttgtctagtg aaagcacttt acaattgcat 6780 tcacgaagac atgaaacgtc ttttacctgt tgtgcgggct ccaaatattg atggctctga 6840 cttgcactct gcagttataa ttacttggat caatatgtct acttctaata aaactagacc 6900 attttttgac aatttactac aggatgaatt acaacacctt aaaaatgcag attataatat 6960 caccacacgc aaaacagtag cagagaatgt ctataggctg aaacatctcc ttttagaaat 7020 tggtttcaac ttggtttata actgtgatga aactgctaat ctttaccact gtcttataga 7080 tgcagatatt cctgttagtt atgtgacccc tgctgatatc agatcttttt taatgacatt 7140 ttcctctcct gacactaatt gccatattgg gaagctgcct tgtcgtctgc agcagactaa 7200 tctaaaactt tttcatagtt taaaactttt agttgattat tgttttaaag atgcagaaga 7260 aaatgagatt gaagttgagg gattgcccct tctcatcaca ctggacagtg ttttgcaaac 7320 ttttgatgca aaacgaccca agtttctaac aacatatcat gaattgattc catcccgcaa 7380 agacttgttt atgaatacat tatatttgaa atatagtaat attttattga actgtaaagt 7440 tgcaaaagtg tttgacattt ccagctttgc tgatttgtta tcctctgtgt tgcctcgaga 7500 atataagacc aaaagttgca caaagtggaa agacaatttt gcaagtgagt cttggcttaa 7560 gaatgcatgg cattttatta gtgaatctgt aagtgtgaaa gaagatcagg aagaaacaaa 7620 accaacattt gacattgttg ttgatactct aaaagactgg gcattgcttc caggaacaaa 7680 gtttactgtt tcagccaacc agcttgtggt tcctgaagga gatgttctgc ttcctctcag 7740 ccttatgcac attgcagttt ttccaaatgc ccagagtgat aaagtttttc atgctctaat 7800 gaaagccggc tgtattcagc ttgctttgaa caaaatctgt tccaaagaca gtgcatttgt 7860 tcctttgttg tcatgtcaca cagcaaatat agagagcccc acaagcatct tgaaggctct 7920 acattatatg gtccaaactt caacatttag agcagaaaaa ttagtagaaa atgattttga 7980 ggcacttttg atgtatttca actgcaattt gaatcatttg atgtcccaag atgatataaa 8040 aattctaaag tcacttccgt gctataaatc catcagtggc cgctatgtaa gcattggaaa 8100 atttggaaca tgctacgtac ttacaaaaag tatcccttca gctgaagtgg agaaatggac 8160 acaatcatca tcatctgcat ttcttgaaga aaaaatacac ttaaaagaac tatatgaggt 8220 gattggttgt gtacctgtag atgatcttga ggtatatttg aaacacctct taccaaaaat 8280 tgaaaatctc tcttatgatg caaaattaga gcacttgatc taccttaaga atagattatc 8340 aagtgctgag gaattatcag agattaagga acaacttttt gaaaaactgg aaagtttatt 8400 gataatccat gatgctaaca gtagactaaa gcaagcaaag catttctatg atagaactgt 8460 gagagttttt gaagttatgc ttcctgaaaa attgtttatt cctaatgatt tctttaagaa 8520 attggaacaa cttataaaac ccaaaaatca tgttacattt atgacatcct gggtggaatt 8580 cttaagaaat attggactaa aatacatact ttctcagcag cagttgttac agtttgctaa 8640 ggaaatcagt gtgagggcta atacagaaaa ctggtccaaa gaaacattgc aaaatacagt 8700 tgatatcctt ctgcatcata tattccaaga acgaatggat ttgttatctg gaaattttct 8760 gaaagaacta tctttaatac cattcttatg tcctgagcgg gcccccgcgg aattcattag 8820 atttcatcct caatatcaag aggtaaatgg aacacttcct cttataaagt tcaatggagc 8880 acaggtaaat ccaaaattca agcaatgtga tgtactccag ctgttatgga catcctgccc 8940 tattcttcca gagaaagcta cacccttaag cattaaagaa caagaaggta gtgaccttgg 9000 tccacaagaa cagcttgaac aagttttaaa tatgcttaat gttaacctgg atcctcctct 9060 tgataaggta atcaataact gcagaaacat atgcaacata acgacgttgg atgaagaaat 9120 ggtaaaaact agagcaaaag tcttaaggag catatatgaa ttcctcagtg cagaaaaaag 9180 ggaatttcgt tttcagttgc gaggggttgc ttttgtgatg gtagaagatg gttggaaact 9240 tctgaagcct gaggaggtag tcataaacct agaatatgaa tctgatttta aaccttattt 9300 gtacaagcta cctttagaac ttggcacatt tcaccagttg ttcaaacact taggtactga 9360 agatattatt tcaactaagc aatatgttga agtgttgagc cgcatattta aaaattctga 9420 gggcaaacaa ttagatccta atgaaatgcg tacagttaag agagtagttt ctggtctgtt 9480 caggagtcta cagaatgatt cagtcaaggt gaggagtgat ctcgagaatg tacgagacct 9540 tgcgctttac ctcccaagcc aggatggtag attggtaaag tcaagcatct tagtgtttga 9600 cgatgcgcca cattataaaa gtagaatcca ggggaatatt ggtgtgcaaa tgttagttga 9660 tctcagccag tgctacttag ggaaagacca tggatttcac actaagttga taatgctctt 9720 tcctcaaaaa cttagacctc gattattgag cagtatactt gaagaacaat tagatgaaga 9780 gactcccaaa gtttgtcagt ttggagcgtt gtgttctctt caaggaagat tgcagttact 9840 cttgtcttct gaacagttca ttacaggact gattagaatt atgaagcatg aaaatgataa 9900 tgcttttctg gccaatgaag aaaaagccat aagactttgc aaagccctaa gagaaggatt 9960 gaaagtatcc tgctttgaaa agcttcaaac aacattaaga gttaaaggtt ttaatcctat 10020 tccccacagc agaagtgaaa cttttgcttt tttgaagcga tttggtaatg cagtcatctt 10080 gctctacatt caacattcag acagtaaaga cattaatttc ctgttagcac tggcaatgac 10140 tcttaaatca gcaactgaca atttgatttc tgacacttca tatttaattg ctatgctagg 10200 atgcaatgat atttacagga ttggtgagaa acttgacagt ttaggagtga aatatgactc 10260 ttcggagcca tcaaaactgg aacttccaat gcctggcaca ccaattcctg ctgaaattca 10320 ttacactctg cttatggacc caatgaatgt tttttacccg ggagaatatg ttgggtacct 10380 tgttgatgct gaaggtggtg atatctatgg atcataccag ccaacataca catatgcaat 10440 tattgtacaa gaagttgaaa gagaagatgc tgacaattct agttttctag gaaagatata 10500 tcagatagat attggttata gtgaatataa aatagttagc tctcttgatc tgtataagtt 10560 ttcaagacct gaggaaagct ctcaaagcag ggacagtgct ccttctacac caaccagccc 10620 cactgagttc ctcacccctg gcctgagaag cattcctcct cttttctctg gtagagagag 10680 ccacaagact tcttccaaac atcagtcccc caaaaagctt aaggttaatt ctttaccaga 10740 aatcttaaaa gaagtgacat ctgtggtgga gcaagcatgg aagcttccag aatcggaacg 10800 aaaaaagatt attaggcggt tgtatttgaa atggcatcct gacaaaaatc cagagaacca 10860 tgacattgcc aatgaagttt ttaaacattt gcagaatgaa atcaacagat tagaaaaaca 10920 ggcttttcta gatcaaaatg cagacagggc ctccagacga acattttcaa cctcagcatc 10980 ccgatttcag tcagacaaat actcatttca gagattctat acttcatgga atcaagaagc 11040 aacgagccat aaatctgaaa gacagcaaca gaacaaagaa aaatgccccc cttcagccgg 11100 acagacttac tctcaaaggt tctttgttcc tcccactttc aagtcggttg gcaatccagt 11160 ggaagcacgc agatggctaa gacaagccag agcaaacttc tcagctgcca ggaatgacct 11220 tcataaaaat gccaatgagt gggtgtgctt taaatgttac ctttctacca agttagcttt 11280 gattgcagct gactatgctg tgaggggaaa gtctgataaa gatgtaaaac caactgcact 11340 tgctcagaaa atagaggaat atagtcagca acttgaagga ctgacaaatg atgttcacac 11400 attggaagct tatggtgtag acagtttaaa aacaagatac cctgatttgc ttccctttcc 11460 tcagatccca aatgacaggt tcacttctga ggttgctatg agggtgatgg aatgtactgc 11520 ctgtatcata ataaaacttg aaaattttat gcaacaaaaa gtgtgaagat atttaacgaa 11580 aaaaaaggta gatcttgaat gtgttgtagc acgaataaat tgctgtactt cattaagctt 11640 cattgccaat tagctaggaa ttgttaagca cattgcagat tgttcttgga gaattctgga 11700 gttgttatga acatgaatac caacggaaaa ccttaactga atctaaaaga aaactatttt 11760 gaagatggtg gtgagctgca aaatagctgg atggatttga atgattggga tgatacatca 11820 ttgaactgca ctttatataa ccaaagctta gcagtttgtt agataagagt ctatgtatgt 11880 ctctggttag gatgaagtta attttatgtt tttaacatgg tatttttgaa ggagctaatg 11940 aaacactgga catataattg gtttaaacat aaggggaatt aagtctttgt agtctgtcat 12000 ttttttaagt ggatcctctt ggatgcgtta ttttctcatc agctggctct gatcatgaat 12060 ttgttgtaat tttatgttgt actcagtgca tttaagaaat ggtagagtat tttaatccta 12120 ttacttgact aagagtgtga aggtagtact ttttagagtg cactgagtgc actttacatc 12180 tttatttaaa ttttttttta acatcttatg tttacaggct tcctgtttga tgaagatagc 12240 aacggaaaac tcaaaatggt ggcagttctt attaccagtt gttagtattg tttctggaaa 12300 ctgcttgcca agacaacatt tattaactgt tagaacactt gctttatgtt tgtgtgtaca 12360 tattttccac aaatgttata atttatatag tgtggttgaa caggatgcaa tcttttgttg 12420 tctaaaggtg ctgcagttaa aaaaaaaaca accttttctt tcaatatggc atgtagtgga 12480 gtttttttaa ctttaaaaac atcaaaaatt gttaaaatca ttgtgttatc tagtagttta 12540 taattatcgg cttatatttc cccatgaatg atcagaactg acatttaatt catgtttgtc 12600 tcgccatgct tctttacttt aacatatttc ttttgcagaa tgtaaaaggt aatgataatt 12660 agtttatata agtgtactgg ctgtaaatga tgctaaatat actttatgca attaagggct 12720 tacagaacat gttgaaactt tttttacttt tattgggaat aaggaatgtt tgcacctcca 12780 cattttattg ctt 12793 <210> SEQ ID NO 12 <211> LENGTH: 12793 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 12 atgatttaca ggaagaccat gtactcagct gcagcttcta aatccagaac gatttgcacg 60 tcttatcaag gaagtaatga atacattctg gcctggcaga gaattgattg ttcaatggta 120 tccatttgat gaaaacagaa atcacccatc tgtttcatgg cttaagatgg tttggaaaaa 180 tctttatata catttttcag aggatttgac tttatttgat gagatgccac ttatccccag 240 aactatacta gaggaaggtc agacatgtgt ggaactcatt agactcagga ttccatcgtt 300 agtcatttta gacgatgaat ctgaagcaca gcttccagaa tttttagcag acattgtaca 360 aaaacttgga gggtttgtcc ttaaaaaatt agatgcatct atacaacatc cgcttattaa 420 aaaatatatt cattcaccat taccaagtgc tgttttgcag ataatggaga agatgccatt 480 gcagaaattg tgtaatcaaa taacttcgct acttccaaca cacaaagatg ccctgaggaa 540 gttcttggct agtttaaccg atagcagtga gaaagagaaa agaattattc aagaattggc 600 aatattcaag cgcattaacc attcttctga tcagggaatt tcctcttata caaaattgaa 660 aggttgtaaa gtcttacacc atactgccaa actcccagca gatctgcgac tttctatttc 720 agtaatagac agtagtgatg aagctactat tcgtctggca aacatgttga aaatagaaca 780 gttaaagacc actagctgct taaagcttgt tttaaaagat attgaaaatg cattttattc 840 acatgaagag gtaacacagc ttatgttatg ggtccttgag aatctatctt ctcttaaaaa 900 tgagaatcca aatgtgcttg agtggttaac accattaaaa ttcatccaga tatcacagga 960 acagatggta tcagctggtg aactctttga ccctgatata gaagtactaa aggatctctt 1020 ttgtaatgaa gaaggaacct atttcccacc ctcagttttt acctcaccag atattcttca 1080 ctccttaaga cagattggtt taaaaaacga agccagtctc aaagaaaagg atgttgtgca 1140 agtggcaaaa aaaattgaag ccttacaggt cggtgcttgt cctgatcaag atgttcttct 1200 gaagaaagcc aaaaccctct tactggtttt aaataagaat cacacactgt tgcaatcatc 1260 tgaaggaaag atgacattga agaaaataaa atgggttcca gcctgcaagg aaaggcctcc 1320 aaattatcca ggctctttgg tctggaaagg agatctctgt aatctctgtg caccaccaga 1380 tatgtgtgat gtaggccatg caattctcat tggctcctca cttcctcttg ttgaaagtat 1440 ccatgtaaac ctggaaaaag cattagggat cttcacaaaa cctagcctta gtgctgtctt 1500 aaaacacttt aaaattgttg ttgattggta ttcttcaaaa acctttagtg atgaagacta 1560 ctatcaattc cagcatattt tgcttgagat ttacggattc atgcatgatc atctaaatga 1620 agggaaagat tcttttagag ccttaaaatt tccatgggtt tggactggca aaaagttttg 1680 tccacttgcc caggctgtga ttaaaccaat ccatgatctt gaccttcagc cttatttgca 1740 taatgtacct aaaaccatgg caaaattcca ccaactattt aaggtctgtg gttcaataga 1800 ggagttgaca tcagatcata tttccatggt tattcagaag atatatctca aaagtgacca 1860 agatctcagt gaacaagaaa gcaaacaaaa tcttcatctt atgttgaata ttatcagatg 1920 gctgtatagc aatcagattc cagcaagccc caacacacca gttcctatac atcatagcaa 1980 aaatccttct aaacttatca tgaagccaat tcacgaatgc tgttattgtg acattaaagt 2040 tgatgacctt aatgacttac ttgaagattc tgtggaacca atcattttgg tgcatgagga 2100 catacccatg aaaactgcag aatggctaaa agttccatgc cttagtacaa gactgataaa 2160 tcctgaaaac atgggatttg agcagtcagg acaaagagag ccacttactg taagaattaa 2220 aaatattctg gaagaatacc cttcagtgtc agatattttt aaagaactac ttcaaaacgc 2280 tgatgatgca aatgcaacag aatgcagttt cttgattgat atgagaagaa atatggacat 2340 aagagagaat ctcctagacc cagggatggc agcttgtcat ggacctgctt tgtggtcatt 2400 caacaattct caattctcag attcagattt tgtgaacata actaggttag gagaatcttt 2460 aaaaagggga gaagttgaca aagttggaaa atttggtctt ggatttaatt ctgtgtacca 2520 tatcactgac attcccatca ttatgagtcg ggaattcatg ataatgttcg atccaaacat 2580 aaatcatatc agtaaacaca ttaaagacaa atccaatcct gggatcaaaa ttaattggag 2640 taaacaacag aaaagactta gaaaatttcc taatcagttc aaaccattta tagatgtatt 2700 tggctgtcag ttacctttga ctgtagaagc accttacagc tataatggaa cccttttccg 2760 actgtccttt agaactcaac aggaagcaaa agtgagtgaa gttagtagta cgtgctacaa 2820 tacagcagat atttattctc ttgtggatga atttagtctc tgtggacaca ggcttatcat 2880 tttcactcag agtgtaaagt caatgtattt gaagtacttg aaaattgagg aaaccaaccc 2940 cagtttagca caagatacag taataattaa aaaaaaatcc tgctcttcca aagcattgaa 3000 cacacctgtc ttaagtgttt taaaagaggc tgctaagctc atgaagactt gcagcagcag 3060 taataaaaag cttcccagtg atgaaccaaa gtcatcttgc attcttcaga tcacagtgga 3120 agaatttcac catgtgttca gaaggattgc tgatttacag tcgccacttt ttagaggtcc 3180 agatgatgac ccagctgctc tctttgaaat ggctaagtct ggccaatcaa aaaagccatc 3240 agatgagttg tcacagaaaa cagtagagtg taccacgtgg cttctgtgta cttgcatgga 3300 cacaggagag gctctgaagt tttccctgag tgagagtgga agaagactag gactggttcc 3360 atgtggggca gtaggagttc agctgtcaga aatccaggac cagaagtgga cagtgaaacc 3420 acacattgga gaggtgtttt gctatttacc tttacgaata aaaacaggct tgccagttca 3480 tatcaatggg tgctttgctg ttacatcaaa taggaaagaa atctggaaaa cagatacaaa 3540 aggacgatgg aataccacgt tcatgagaca tgttattgtg aaagcttact tacaggtact 3600 gagtgtctta cgggacctgg ccactagtgg ggagctaatg gattatactt actatgcagt 3660 atggcccgat cctgatttag ttcatgatga tttttctgta atttgccaag gattttatga 3720 agatatagct catggaaaag ggaaagaact gaccaaagtc ttctctgatg gatctacttg 3780 ggtttccatg aagaacgtaa gatttctaga tgactctata cttaaaagaa gagatgttgg 3840 ttcagcagcc ttcaagatat ttttgaaata cctcaagaag actgggtcca aaaacctttg 3900 tgctgttgaa cttccttctt cggtaaaatt aggatttgaa gaagctggct gcaaacagat 3960 actacttgaa aacacatttt cagagaaaca gtttttttct gaagtgtttt ttccaaatat 4020 tcaagaaatt gaagcagaac ttagagatcc tttaatgatc tttgttctaa atgaaaaagt 4080 tgatgagttc tcgggagttc ttcgtgttac tccatgtatt ccttgttcct tggaggggca 4140 tcctttggtt ttgccatcaa gattgatcca ccccgaagga cgagttgcaa agttatttga 4200 tattaaagat gggagattcc cttatggttc tactcaggat tatctcaatc ctattatttt 4260 gattaaacta gttcagttag gtatggcaaa agatgatatt ttatgggatg atatgctaga 4320 acgtgcagtg tcagtagctg aaattaataa aagtgatcat gttgctgcat gcctaagaag 4380 tagtatctta ttgagtctta tcgatgagaa actaaaaata agggatccta gagcaaagga 4440 ttttgctgca aaatatcaaa caatccgctt ccttccattt ctgacaaaac cagcaggttt 4500 ttctttggac tggaaaggca acagttttaa gcctgaaacc atgtttgcag caactgacct 4560 ttatacagct gaacatcaag atatagtttg tcttttgcaa ccaattctaa atgaaaattc 4620 ccattctttt agaggttgtg gttcagtgtc attggctgtt aaagagtttt tgggattact 4680 caagaagcca acagttgatc tggttataaa ccaattgaaa gaagtagcaa aatcagttga 4740 tgatggaatt acactgtacc aggagaatat caccaatgct tgctacaaat accttcatga 4800 agccttgatg caaaatgaaa tcactaagat gtcaattatt gataagttaa aaccctttag 4860 cttcattcta gttgagaatg catatgttga ctcagaaaag gtttcttttc atttaaattt 4920 tgaggcggca ccataccttt atcagttgcc taataagtat aaaaataatt tccgcgaact 4980 ttttgaaacc gtgggtgtga ggcagtcatg cactgttgaa gattttgctc ttgttttgga 5040 atctattgat caagaaagag gaacaaagca aataacagaa gagaattttc agctttgccg 5100 acgaataatc agtgaaggaa tatggagtct cattagagaa aagaaacaag aattttgtga 5160 gaaaaattat ggcaagatat tattgccaga tactaatctt atgcttctcc ctgctaaatc 5220 gttatgctac aatgattgcc cttggataaa agtaaaggat accactgtaa aatattgtca 5280 tgctgacata cccagggaag tagcagtaaa actaggagca gtcccaaagc gacacaaagc 5340 cttagaaaga tatgcatcca atgtctgttt tacaacactt ggcacagaat ttgggcagaa 5400 agaaaaattg accagcagaa ttaagagcat ccttaatgca tatccttctg aaaaggaaat 5460 gttgaaagag cttcttcaaa atgctgatga tgcaaaggcg acagaaatct gttttgtgtt 5520 tgatcctaga cagcatccag ttgatagaat atttgatgat aagtgggccc cattgcaagg 5580 gccagcactt tgtgtgtaca acaaccagcc atttacagaa gatgatgtta gaggaattca 5640 gaatcttgga aaaggcacga aagagggaaa tccttataaa actggacagt atggaatagg 5700 attcaattct gtgtatcata tcacagactg cccatctttt atttctggca atgacatcct 5760 gtgtattttt gatcctcatg ccagatatgc accaggggcc acatccatta gtcccggacg 5820 catgtttaga gatttggatg cagattttag gacacagttc tcagatgttc tggatcttta 5880 tctgggaacc cattttaaac tggataattg cacaatgttc agatttcctc ttcgtaatgc 5940 agaaatggca aaagtttcgg aaatttcgtc tgttccagca tcagacagaa tggtccagaa 6000 tcttttggac aaactgcgct cagatggggc agaacttcta atgtttctta atcacatgga 6060 aaaaatttct atttgtgaaa tagataagag tactggagct ctaaatgtgc tgtattcagt 6120 aaagggcaaa atcacagatg gagacagatt gaaaaggaaa caatttcatg catctgtaat 6180 tgatagtgtt actaaaaaga ggcagctcaa agacatacca gttcaacaaa taacctatac 6240 tatggatact gaggactctg aaggaaatct tactacgtgg ctaatttgta atagatcagg 6300 cttttcaagt atggagaaag tatctaaaag tgtcatatca gctcacaaga accaagatat 6360 tactcttttc ccacgtggtg gagtagctgc ctgcattact cacaactata aaaaacccca 6420 tagggccttc tgttttttgc ctctttcttt ggagactggg ctgccatttc atgtgaatgg 6480 ccactttgca ctggattcag ccagaaggaa cctgtggcgt gatgataatg gagttggtgt 6540 tcgaagtgac tggaataaca gtttaatgac agcattaata gctcctgcat atgttgaatt 6600 gccaatacag ttaaaaaaac ggtatttccc tggttctgat ccaacattat cagtgttaca 6660 gaacacccct attcatgttg taaaggacac tttaaagaag tttttatcgt ttttcccagt 6720 taaccgtctt gatctacagc cagatttata ttgtctagtg aaagcacttt acaattgcat 6780 tcacgaagac atgaaacgtc ttttacctgt tgtgcgggct ccaaatattg atggctctga 6840 cttgcactct gcagttataa ttacttggat caatatgtct acttctaata aaactagacc 6900 attttttgac aatttactac aggatgaatt acaacacctt aaaaatgcag attataatat 6960 caccacacgc aaaacagtag cagagaatgt ctataggctg aaacatctcc ttttagaaat 7020 tggtttcaac ttggtttata actgtgatga aactgctaat ctttaccact gtcttataga 7080 tgcagatatt cctgttagtt atgtgacccc tgctgatatc agatcttttt taatgacatt 7140 ttcctctcct gacactaatt gccatattgg gaagctgcct tgtcgtctgc agcagactaa 7200 tctaaaactt tttcatagtt taaaactttt agttgattat tgttttaaag atgcagaaga 7260 aaatgagatt gaagttgagg gattgcccct tctcatcaca ctggacagtg ttttgcaaac 7320 ttttgatgca aaacgaccca agtttctaac aacatatcat gaattgattc catcccgcaa 7380 agacttgttt atgaatacat tatatttgaa atatagtaat attttattga actgtaaagt 7440 tgcaaaagtg tttgacattt ccagctttgc tgatttgtta tcctctgtgt tgcctcgaga 7500 atataagacc aaaagttgca caaagtggaa agacaatttt gcaagtgagt cttggcttaa 7560 gaatgcatgg cattttatta gtgaatctgt aagtgtgaaa gaagatcagg aagaaacaaa 7620 accaacattt gacattgttg ttgatactct aaaagactgg gcattgcttc caggaacaaa 7680 gtttactgtt tcagccaacc agcttgtggt tcctgaagga gatgttctgc ttcctctcag 7740 ccttatgcac attgcagttt ttccaaatgc ccagagtgat aaagtttttc atgctctaat 7800 gaaagccggc tgtattcagc ttgctttgaa caaaatctgt tccaaagaca gtgcatttgt 7860 tcctttgttg tcatgtcaca cagcaaatat agagagcccc acaagcatct tgaaggctct 7920 acattatatg gtccaaactt caacatttag agcagaaaaa ttagtagaaa atgattttga 7980 ggcacttttg atgtatttca actgcaattt gaatcatttg atgtcccaag atgatataaa 8040 aattctaaag tcacttccgt gctataaatc catcagtggc cgctatgtaa gcattggaaa 8100 atttggaaca tgctacgtac ttacaaaaag tatcccttca gctgaagtgg agaaatggac 8160 acaatcatca tcatctgcat ttcttgaaga aaaaatacac ttaaaagaac tatatgaggt 8220 gattggttgt gtacctgtag atgatcttga ggtatatttg aaacacctct taccaaaaat 8280 tgaaaatctc tcttatgatg caaaattaga gcacttgatc taccttaaga atagattatc 8340 aagtgctgag gaattatcag agattaagga acaacttttt gaaaaactgg aaagtttatt 8400 gataatccat gatgctaaca gtagactaaa gcaagcaaag catttctatg atagaactgt 8460 gagagttttt gaagttatgc ttcctgaaaa attgtttatt cctaatgatt tctttaagaa 8520 attggaacaa cttataaaac ccaaaaatca tgttacattt atgacatcct gggtggaatt 8580 cttaagaaat attggactaa aatacatact ttctcagcag cagttgttac agtttgctaa 8640 ggaaatcagt gtgagggcta atacagaaaa ctggtccaaa gaaacattgc aaaatacagt 8700 tgatatcctt ctgcatcata tattccaaga acgaatggat ttgttatctg gaaattttct 8760 gaaagaacta tctttaatac cattcttatg tcctgagcgg gcccccgcgg aattcattag 8820 atttcatcct caatatcaag aggtaaatgg aacacttcct cttataaagt tcaatggagc 8880 acaggtaaat ccaaaattca agcaatgtga tgtactccag ctgttatgga catcctgccc 8940 tattcttcca gagaaagcta cacccttaag cattaaagaa caagaaggta gtgaccttgg 9000 tccacaagaa cagcttgaac aagttttaaa tatgcttaat gttaacctgg atcctcctct 9060 tgataaggta atcaataact gcagaaacat atgcaacata acgacgttgg atgaagaaat 9120 ggtaaaaact agagcaaaag tcttaaggag catatatgaa ttcctcagtg cagaaaaaag 9180 ggaatttcgt tttcagttgc gaggggttgc ttttgtgatg gtagaagatg gttggaaact 9240 tctgaagcct gaggaggtag tcataaacct agaatatgaa tctgatttta aaccttattt 9300 gtacaagcta cctttagaac ttggcacatt tcaccagttg ttcaaacact taggtactga 9360 agatattatt tcaactaagc aatatgttga agtgttgagc cgcatattta aaaattctga 9420 gggcaaacaa ttagatccta atgaaatgcg tacagttaag agagtagttt ctggtctgtt 9480 caggagtcta cagaatgatt cagtcaaggt gaggagtgat ctcgagaatg tacgagacct 9540 tgcgctttac ctcccaagcc aggatggtag attggtaaag tcaagcatct tagtgtttga 9600 cgatgcgcca cattataaaa gtagaatcca ggggaatatt ggtgtgcaaa tgttagttga 9660 tctcagccag tgctacttag ggaaagacca tggatttcac actaagttga taatgctctt 9720 tcctcaaaaa cttagacctc gattattgag cagtatactt gaagaacaat tagatgaaga 9780 gactcccaaa gtttgtcagt ttggagcgtt gtgttctctt caaggaagat tgcagttact 9840 cttgtcttct gaacagttca ttacaggact gattagaatt atgaagcatg aaaatgataa 9900 tgcttttctg gccaatgaag aaaaagccat aagactttgc aaagccctaa gagaaggatt 9960 gaaagtatcc tgctttgaaa agcttcaaac aacattaaga gttaaaggtt ttaatcctat 10020 tccccacagc agaagtgaaa cttttgcttt tttgaagcga tttggtaatg cagtcatctt 10080 gctctacatt caacattcag acagtaaaga cattaatttc ctgttagcac tggcaatgac 10140 tcttaaatca gcaactgaca atttgatttc tgacacttca tatttaattg ctatgctagg 10200 atgcaatgat atttacagga ttggtgagaa acttgacagt ttaggagtga aatatgactc 10260 ttcggagcca tcaaaactgg aacttccaat gcctggcaca ccaattcctg ctgaaattca 10320 ttacactctg cttatggacc caatgaatgt tttttacccg ggagaatatg ttgggtacct 10380 tgttgatgct gaaggtggtg atatctatgg atcataccag ccaacataca catatgcaat 10440 tattgtacaa gaagttgaaa gagaagatgc tgacaattct agttttctag gaaagatata 10500 tcagatagat attggttata gtgaatataa aatagttagc tctcttgatc tgtataagtt 10560 ttcaagacct gaggaaagct ctcaaagcag ggacagtgct ccttctacac caaccagccc 10620 cactgagttc ctcacccctg gcctgagaag cattcctcct cttttctctg gtagagagag 10680 ccacaagact tcttccaaac atcagtcccc caaaaagctt aaggttaatt ctttaccaga 10740 aatcttaaaa gaagtgacat ctgtggtgga gcaagcatgg aagcttccag aatcggaacg 10800 aaaaaagatt attaggcggt tgtatttgaa atggcatcct gacaaaaatc cagagaacca 10860 tgacattgcc aatgaagttt ttaaacattt gcagaatgaa atcaacagat tagaaaaaca 10920 ggcttttcta gatcaaaatg cagacagggc ctccagacga acattttcaa cctcagcatc 10980 ccgatttcag tcagacaaat actcatttca gagattctat acttcatgga atcaagaagc 11040 aacgagccat aaatctgaaa gacagcaaca gaacaaagaa aaatgccccc cttcagccgg 11100 acagacttac tctcaaaggt tctttgttcc tcccactttc aagtcggttg gcaatccagt 11160 ggaagcacgc agatggctaa gacaagccag agcaaacttc tcagctgcca ggaatgacct 11220 tcataaaaat gccaatgagt gggtgtgctt taaatgttac ctttctacca agttagcttt 11280 gattgcagct gactatgctg tgaggggaaa gtctgataaa gatgtaaaac caactgcact 11340 tgctcagaaa atagaggaat atagtcagca acttgaagga ctgacaaatg atgttcacac 11400 attggaagct tatggtgtag acagtttaaa aacaagatac cctgatttgc ttccctttcc 11460 tcagatccca aatgacaggt tcacttctga ggttgctatg agggtgatgg aatgtactgc 11520 ctgtatcata ataaaacttg aaaattttat gcaacaaaaa gtgtgaagat atttaacgaa 11580 aaaaaaggta gatcttgaat gtgttgtagc acgaataaat tgctgtactt cattaagctt 11640 cattgccaat tagctaggaa ttgttaagca cattgcagat tgttcttgga gaattctgga 11700 gttgttatga acatgaatac caacggaaaa ccttaactga atctaaaaga aaactatttt 11760 gaagatggtg gtgagctgca aaatagctgg atggatttga atgattggga tgatacatca 11820 ttgaactgca ctttatataa ccaaagctta gcagtttgtt agataagagt ctatgtatgt 11880 ctctggttag gatgaagtta attttatgtt tttaacatgg tatttttgaa ggagctaatg 11940 aaacactgga catataattg gtttaaacat aaggggaatt aagtctttgt agtctgtcat 12000 ttttttaagt ggatcctctt ggatgcgtta ttttctcatc agctggctct gatcatgaat 12060 ttgttgtaat tttatgttgt actcagtgca tttaagaaat ggtagagtat tttaatccta 12120 ttacttgact aagagtgtga aggtagtact ttttagagtg cactgagtgc actttacatc 12180 tttatttaaa ttttttttta acatcttatg tttacaggct tcctgtttga tgaagatagc 12240 aacggaaaac tcaaaatggt ggcagttctt attaccagtt gttagtattg tttctggaaa 12300 ctgcttgcca agacaacatt tattaactgt tagaacactt gctttatgtt tgtgtgtaca 12360 tattttccac aaatgttata atttatatag tgtggttgaa caggatgcaa tcttttgttg 12420 tctaaaggtg ctgcagttaa aaaaaaaaca accttttctt tcaatatggc atgtagtgga 12480 gtttttttaa ctttaaaaac atcaaaaatt gttaaaatca ttgtgttatc tagtagttta 12540 taattatcgg cttatatttc cccatgaatg atcagaactg acatttaatt catgtttgtc 12600 tcgccatgct tctttacttt aacatatttc ttttgcagaa tgtaaaaggt aatgataatt 12660 agtttatata agtgtactgg ctgtaaatga tgctaaatat actttatgca attaagggct 12720 tacagaacat gttgaaactt tttttacttt tattgggaat aaggaatgtt tgcacctcca 12780 cattttattg ctt 12793 <210> SEQ ID NO 13 <211> LENGTH: 12717 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 13 atgaatacat tctggcctgg cagagaattg attgttcaat ggtatccatt tgatgaaaac 60 agaaatcacc catctgtttc atggcttaag atggtttgga aaaatcttta tatacatttt 120 tcagaggatt tgactttatt tgatgagatg ccacttatcc ccagaactat actagaggaa 180 ggtcagacat gtgtggaact cattagactc aggattccat cgttagtcat tttagacgat 240 gaatctgaag cacagcttcc agaattttta gcagacattg tacaaaaact tggagggttt 300 gtccttaaaa aattagatgc atctatacaa catccgctta ttaaaaaata tattcattca 360 ccattaccaa gtgctgtttt gcagataatg gagaagatgc cattgcagaa attgtgtaat 420 caaataactt cgctacttcc aacacacaaa gatgccctga ggaagttctt ggctagttta 480 accgatagca gtgagaaaga gaaaagaatt attcaagaat tggcaatatt caagcgcatt 540 aaccattctt ctgatcaggg aatttcctct tatacaaaat tgaaaggttg taaagtctta 600 caccatactg ccaaactccc agcagatctg cgactttcta tttcagtaat agacagtagt 660 gatgaagcta ctattcgtct ggcaaacatg ttgaaaatag aacagttaaa gaccactagc 720 tgcttaaagc ttgttttaaa agatattgaa aatgcatttt attcacatga agaggtaaca 780 cagcttatgt tatgggtcct tgagaatcta tcttctctta aaaatgagaa tccaaatgtg 840 cttgagtggt taacaccatt aaaattcatc cagatatcac aggaacagat ggtatcagct 900 ggtgaactct ttgaccctga tatagaagta ctaaaggatc tcttttgtaa tgaagaagga 960 acctatttcc caccctcagt ttttacctca ccagatattc ttcactcctt aagacagatt 1020 ggtttaaaaa acgaagccag tctcaaagaa aaggatgttg tgcaagtggc aaaaaaaatt 1080 gaagccttac aggtcggtgc ttgtcctgat caagatgttc ttctgaagaa agccaaaacc 1140 ctcttactgg ttttaaataa gaatcacaca ctgttgcaat catctgaagg aaagatgaca 1200 ttgaagaaaa taaaatgggt tccagcctgc aaggaaaggc ctccaaatta tccaggctct 1260 ttggtctgga aaggagatct ctgtaatctc tgtgcaccac cagatatgtg tgatgtaggc 1320 catgcaattc tcattggctc ctcacttcct cttgttgaaa gtatccatgt aaacctggaa 1380 aaagcattag ggatcttcac aaaacctagc cttagtgctg tcttaaaaca ctttaaaatt 1440 gttgttgatt ggtattcttc aaaaaccttt agtgatgaag actactatca attccagcat 1500 attttgcttg agatttacgg attcatgcat gatcatctaa atgaagggaa agattctttt 1560 agagccttaa aatttccatg ggtttggact ggcaaaaagt tttgtccact tgcccaggct 1620 gtgattaaac caatccatga tcttgacctt cagccttatt tgcataatgt acctaaaacc 1680 atggcaaaat tccaccaact atttaaggtc tgtggttcaa tagaggagtt gacatcagat 1740 catatttcca tggttattca gaagatatat ctcaaaagtg accaagatct cagtgaacaa 1800 gaaagcaaac aaaatcttca tcttatgttg aatattatca gatggctgta tagcaatcag 1860 attccagcaa gccccaacac accagttcct atacatcata gcaaaaatcc ttctaaactt 1920 atcatgaagc caattcacga atgctgttat tgtgacatta aagttgatga ccttaatgac 1980 ttacttgaag attctgtgga accaatcatt ttggtgcatg aggacatacc catgaaaact 2040 gcagaatggc taaaagttcc atgccttagt acaagactga taaatcctga aaacatggga 2100 tttgagcagt caggacaaag agagccactt actgtaagaa ttaaaaatat tctggaagaa 2160 tacccttcag tgtcagatat ttttaaagaa ctacttcaaa acgctgatga tgcaaatgca 2220 acagaatgca gtttcttgat tgatatgaga agaaatatgg acataagaga gaatctccta 2280 gacccaggga tggcagcttg tcatggacct gctttgtggt cattcaacaa ttctcaattc 2340 tcagattcag attttgtgaa cataactagg ttaggagaat ctttaaaaag gggagaagtt 2400 gacaaagttg gaaaatttgg tcttggattt aattctgtgt accatatcac tgacattccc 2460 atcattatga gtcgggaatt catgataatg ttcgatccaa acataaatca tatcagtaaa 2520 cacattaaag acaaatccaa tcctgggatc aaaattaatt ggagtaaaca acagaaaaga 2580 cttagaaaat ttcctaatca gttcaaacca tttatagatg tatttggctg tcagttacct 2640 ttgactgtag aagcacctta cagctataat ggaacccttt tccgactgtc ctttagaact 2700 caacaggaag caaaagtgag tgaagttagt agtacgtgct acaatacagc agatatttat 2760 tctcttgtgg atgaatttag tctctgtgga cacaggctta tcattttcac tcagagtgta 2820 aagtcaatgt atttgaagta cttgaaaatt gaggaaacca accccagttt agcacaagat 2880 acagtaataa ttaaaaaaaa atcctgctct tccaaagcat tgaacacacc tgtcttaagt 2940 gttttaaaag aggctgctaa gctcatgaag acttgcagca gcagtaataa aaagcttccc 3000 agtgatgaac caaagtcatc ttgcattctt cagatcacag tggaagaatt tcaccatgtg 3060 ttcagaagga ttgctgattt acagtcgcca ctttttagag gtccagatga tgacccagct 3120 gctctctttg aaatggctaa gtctggccaa tcaaaaaagc catcagatga gttgtcacag 3180 aaaacagtag agtgtaccac gtggcttctg tgtacttgca tggacacagg agaggctctg 3240 aagttttccc tgagtgagag tggaagaaga ctaggactgg ttccatgtgg ggcagtagga 3300 gttcagctgt cagaaatcca ggaccagaag tggacagtga aaccacacat tggagaggtg 3360 ttttgctatt tacctttacg aataaaaaca ggcttgccag ttcatatcaa tgggtgcttt 3420 gctgttacat caaataggaa agaaatctgg aaaacagata caaaaggacg atggaatacc 3480 acgttcatga gacatgttat tgtgaaagct tacttacagg tactgagtgt cttacgggac 3540 ctggccacta gtggggagct aatggattat acttactatg cagtatggcc cgatcctgat 3600 ttagttcatg atgatttttc tgtaatttgc caaggatttt atgaagatat agctcatgga 3660 aaagggaaag aactgaccaa agtcttctct gatggatcta cttgggtttc catgaagaac 3720 gtaagatttc tagatgactc tatacttaaa agaagagatg ttggttcagc agccttcaag 3780 atatttttga aatacctcaa gaagactggg tccaaaaacc tttgtgctgt tgaacttcct 3840 tcttcggtaa aattaggatt tgaagaagct ggctgcaaac agatactact tgaaaacaca 3900 ttttcagaga aacagttttt ttctgaagtg ttttttccaa atattcaaga aattgaagca 3960 gaacttagag atcctttaat gatctttgtt ctaaatgaaa aagttgatga gttctcggga 4020 gttcttcgtg ttactccatg tattccttgt tccttggagg ggcatccttt ggttttgcca 4080 tcaagattga tccaccccga aggacgagtt gcaaagttat ttgatattaa agatgggaga 4140 ttcccttatg gttctactca ggattatctc aatcctatta ttttgattaa actagttcag 4200 ttaggtatgg caaaagatga tattttatgg gatgatatgc tagaacgtgc agtgtcagta 4260 gctgaaatta ataaaagtga tcatgttgct gcatgcctaa gaagtagtat cttattgagt 4320 cttatcgatg agaaactaaa aataagggat cctagagcaa aggattttgc tgcaaaatat 4380 caaacaatcc gcttccttcc atttctgaca aaaccagcag gtttttcttt ggactggaaa 4440 ggcaacagtt ttaagcctga aaccatgttt gcagcaactg acctttatac agctgaacat 4500 caagatatag tttgtctttt gcaaccaatt ctaaatgaaa attcccattc ttttagaggt 4560 tgtggttcag tgtcattggc tgttaaagag tttttgggat tactcaagaa gccaacagtt 4620 gatctggtta taaaccaatt gaaagaagta gcaaaatcag ttgatgatgg aattacactg 4680 taccaggaga atatcaccaa tgcttgctac aaataccttc atgaagcctt gatgcaaaat 4740 gaaatcacta agatgtcaat tattgataag ttaaaaccct ttagcttcat tctagttgag 4800 aatgcatatg ttgactcaga aaaggtttct tttcatttaa attttgaggc ggcaccatac 4860 ctttatcagt tgcctaataa gtataaaaat aatttccgcg aactttttga aaccgtgggt 4920 gtgaggcagt catgcactgt tgaagatttt gctcttgttt tggaatctat tgatcaagaa 4980 agaggaacaa agcaaataac agaagagaat tttcagcttt gccgacgaat aatcagtgaa 5040 ggaatatgga gtctcattag agaaaagaaa caagaatttt gtgagaaaaa ttatggcaag 5100 atattattgc cagatactaa tcttatgctt ctccctgcta aatcgttatg ctacaatgat 5160 tgcccttgga taaaagtaaa ggataccact gtaaaatatt gtcatgctga catacccagg 5220 gaagtagcag taaaactagg agcagtccca aagcgacaca aagccttaga aagatatgca 5280 tccaatgtct gttttacaac acttggcaca gaatttgggc agaaagaaaa attgaccagc 5340 agaattaaga gcatccttaa tgcatatcct tctgaaaagg aaatgttgaa agagcttctt 5400 caaaatgctg atgatgcaaa ggcgacagaa atctgttttg tgtttgatcc tagacagcat 5460 ccagttgata gaatatttga tgataagtgg gccccattgc aagggccagc actttgtgtg 5520 tacaacaacc agccatttac agaagatgat gttagaggaa ttcagaatct tggaaaaggc 5580 acgaaagagg gaaatcctta taaaactgga cagtatggaa taggattcaa ttctgtgtat 5640 catatcacag actgcccatc ttttatttct ggcaatgaca tcctgtgtat ttttgatcct 5700 catgccagat atgcaccagg ggccacatcc attagtcccg gacgcatgtt tagagatttg 5760 gatgcagatt ttaggacaca gttctcagat gttctggatc tttatctggg aacccatttt 5820 aaactggata attgcacaat gttcagattt cctcttcgta atgcagaaat ggcaaaagtt 5880 tcggaaattt cgtctgttcc agcatcagac agaatggtcc agaatctttt ggacaaactg 5940 cgctcagatg gggcagaact tctaatgttt cttaatcaca tggaaaaaat ttctatttgt 6000 gaaatagata agagtactgg agctctaaat gtgctgtatt cagtaaaggg caaaatcaca 6060 gatggagaca gattgaaaag gaaacaattt catgcatctg taattgatag tgttactaaa 6120 aagaggcagc tcaaagacat accagttcaa caaataacct atactatgga tactgaggac 6180 tctgaaggaa atcttactac gtggctaatt tgtaatagat caggcttttc aagtatggag 6240 aaagtatcta aaagtgtcat atcagctcac aagaaccaag atattactct tttcccacgt 6300 ggtggagtag ctgcctgcat tactcacaac tataaaaaac cccatagggc cttctgtttt 6360 ttgcctcttt ctttggagac tgggctgcca tttcatgtga atggccactt tgcactggat 6420 tcagccagaa ggaacctgtg gcgtgatgat aatggagttg gtgttcgaag tgactggaat 6480 aacagtttaa tgacagcatt aatagctcct gcatatgttg aattgctaat acagttaaaa 6540 aaacggtatt tccctggttc tgatccaaca ttatcagtgt tacagaacac ccctattcat 6600 gttgtaaagg acactttaaa gaagttttta tcgtttttcc cagttaaccg tcttgatcta 6660 cagccagatt tatattgtct agtgaaagca ctttacaatt gcattcacga agacatgaaa 6720 cgtcttttac ctgttgtgcg ggctccaaat attgatggct ctgacttgca ctctgcagtt 6780 ataattactt ggatcaatat gtctacttct aataaaacta gaccattttt tgacaattta 6840 ctacaggatg aattacaaca ccttaaaaat gcagattata atatcaccac acgcaaaaca 6900 gtagcagaga atgtctatag gctgaaacat ctccttttag aaattggttt caacttggtt 6960 tataactgtg atgaaactgc taatctttac cactgtctta tagatgcaga tattcctgtt 7020 agttatgtga cccctgctga tatcagatct tttttaatga cattttcctc tcctgacact 7080 aattgccata ttgggaagct gccttgtcgt ctgcagcaga ctaatctaaa actttttcat 7140 agtttaaaac ttttagttga ttattgtttt aaagatgcag aagaaaatga gattgaagtt 7200 gagggattgc cccttctcat cacactggac agtgttttgc aaacttttga tgcaaaacga 7260 cccaagtttc taacaacata tcatgaattg attccatccc gcaaagactt gtttatgaat 7320 acattatatt tgaaatatag taatatttta ttgaactgta aagttgcaaa agtgtttgac 7380 atttccagct ttgctgattt gttatcctct gtgttgcctc gagaatataa gaccaaaagt 7440 tgcacaaagt ggaaagacaa ttttgcaagt gagtcttggc ttaagaatgc atggcatttt 7500 attagtgaat ctgtaagtgt gaaagaagat caggaagaaa caaaaccaac atttgacatt 7560 gttgttgata ctctaaaaga ctgggcattg cttccaggaa caaagtttac tgtttcagcc 7620 aaccagcttg tggttcctga aggagatgtt ctgcttcctc tcagccttat gcacattgca 7680 gtttttccaa atgcccagag tgataaagtt tttcatgctc taatgaaagc tggctgtatt 7740 cagcttgctt tgaacaaaat ctgttccaaa gacagtgcat ttgttccttt gttgtcatgt 7800 cacacagcaa atatagagag ccccacaagc atcttgaagg ctctacatta tatggtccaa 7860 acttcaacat ttagagcaga aaaattagta gaaaatgatt ttgaggcact tttgatgtat 7920 ttcaactgca atttgaatca tttgatgtcc caagatgata taaaaattct aaagtcactt 7980 ccgtgctata aatccatcag tggccgctat gtaagcattg gaaaatttgg aacatgctac 8040 gtacttacaa aaagtatccc ttcagctgaa gtggagaaat ggacacaatc atcatcatct 8100 gcatttcttg aagaaaaaat acacttaaaa gaactatatg aggtgattgg ttgtgtacct 8160 gtagatgatc ttgaggtata tttgaaacac ctcttaccaa aaattgaaaa tctctcttat 8220 gatgcaaaat tagagcactt gatctacctt aagaatagat tatcaagtgc tgaggaatta 8280 tcagagatta aggaacaact ttttgaaaaa ctggaaagtt tattgataat ccatgatgct 8340 aacagtagac taaagcaagc aaagcatttc tatgatagaa ctgtgagagt ttttgaagtt 8400 atgcttcctg aaaaattgtt tattcctaat gatttcttta agaaattgga acaacttata 8460 aaacccaaaa atcatgttac atttatgaca tcctgggtgg aattcttaag aaatattgga 8520 ctaaaataca tactttctca gcagcagttg ttacagtttg ctaaggaaat cagtgtgagg 8580 gctaatacag aaaactggtc caaagaaaca ttgcaaaata cagttgatat ccttctgcat 8640 catatattcc aagaacgaat ggatttgtta tctggaaatt ttctgaaaga actatcttta 8700 ataccattct tatgtcctga gcgggccccc gcggaattca ttagatttca tcctcaatat 8760 caagaggtaa atggaacact tcctcttata aagttcaatg gagcacaggt aaatccaaaa 8820 ttcaagcaat gtgatgtact ccagctgtta tggacatcct gccctattct tccagagaaa 8880 gctacaccct taagcattaa agaacaagaa ggtagtgacc ttggtccaca agaacagctt 8940 gaacaagttt taaatatgct taatgttaac ctggatcctc ctcttgataa ggtaatcaat 9000 aactgcagaa acatatgcaa cataacgacg ttggatgaag aaatggtaaa aactagagca 9060 aaagtcttaa ggagcatata tgaattcctc agtgcagaaa aaagggaatt tcgttttcag 9120 ttgcgagggg ttgcttttgt gatggtagaa gatggttgga aacttctgaa gcctgaggag 9180 gtagtcataa acctagaata tgaatctgat tttaaacctt atttgtacaa gctaccttta 9240 gaacttggca catttcacca gttgttcaaa cacttaggta ctgaagatat tatttcaact 9300 aagcaatatg ttgaagtgtt gagccgcata tttaaaaatt ctgagggcaa acaattagat 9360 cctaatgaaa tgcgtacagt taagagagta gtttctggtc tgttcaggag tctacagaat 9420 gattcagtca aggtgaggag tgatctcgag aatgtacgag accttgcgct ttacctccca 9480 agccaggatg gtagattggt aaagtcaagc atcttagtgt ttgacgatgc gccacattat 9540 aaaagtagaa tccaggggaa tattggtgtg caaatgttag ttgatctcag ccagtgctac 9600 ttagggaaag accatggatt tcacactaag ttgataatgc tctttcctca aaaacttaga 9660 cctcgattat tgagcagtat acttgaagaa caattagatg aagagactcc caaagtttgt 9720 cagtttggag cgttgtgttc tcttcaagga agattgcagt tactcttgtc ttctgaacag 9780 ttcattacag gactgattag aattatgaag catgaaaatg ataatgcttt tctggccaat 9840 gaagaaaaag ccataagact ttgcaaagcc ctaagagaag gattgaaagt atcctgcttt 9900 gaaaagcttc aaacaacatt aagagttaaa ggttttaatc ctattcccca cagcagaagt 9960 gaaacttttg cttttttgaa gcgatttggt aatgcagtca tcttgctcta cattcaacat 10020 tcagacagta aagacattaa tttcctgtta gcactggcaa tgactcttaa atcagcaact 10080 gacaatttga tttctgacac ttcatattta attgctatgc taggatgcaa tgatatttac 10140 aggattggtg agaaacttga cagtttagga gtgaaatatg actcttcgga gccatcaaaa 10200 ctggaacttc caatgcctgg cacaccaatt cctgctgaaa ttcattacac tctgcttatg 10260 gacccaatga atgtttttta cccgggagaa tatgttgggt accttgttga tgctgaaggt 10320 ggtgatatct atggatcata ccagccaaca tacacatatg caattattgt acaagaagtt 10380 gaaagagaag atgctgacaa ttctagtttt ctaggaaaga tatatcagat agatattggt 10440 tatagtgaat ataaaatagt tagctctctt gatctgtata agttttcaag acctgaggaa 10500 agctctcaaa gcagggacag tgctccttct acaccaacca gccccactga gttcctcacc 10560 cctggcctga gaagcattcc tcctcttttc tctggtagag agagccacaa gacttcttcc 10620 aaacatcagt cccccaaaaa gcttaaggtt aattctttac cagaaatctt aaaagaagtg 10680 acatctgtgg tggagcaagc atggaagctt ccagaatcgg aacgaaaaaa gattattagg 10740 cggttgtatt tgaaatggca tcctgacaaa aatccagaga accatgacat tgccaatgaa 10800 gtttttaaac atttgcagaa tgaaatcaac agattagaaa aacaggcttt tctagatcaa 10860 aatgcagaca gggcctccag acgaacattt tcaacctcag catcccgatt tcagtcagac 10920 aaatactcat ttcagagatt ctatacttca tggaatcaag aagcaacgag ccataaatct 10980 gaaagacagc aacagaacaa agaaaaatgc cccccttcag ccggacagac ttactctcaa 11040 aggttctttg ttcctcccac tttcaagtcg gttggcaatc cagtggaagc acgcagatgg 11100 ctaagacaag ccagagcaaa cttctcagct gccaggaatg accttcataa aaatgccaat 11160 gagtgggtgt gctttaaatg ttacctttct accaagttag ctttgattgc agctgactat 11220 gctgtgaggg gaaagtctga taaagatgta aaaccaactg cacttgctca gaaaatagag 11280 gaatatagtc agcaacttga aggactgaca aatgatgttc acacattgga agcttatggt 11340 gtagacagtt taaaaacaag ataccctgat ttgcttccct ttcctcagat cccaaatgac 11400 aggttcactt ctgaggttgc tatgagggtg atggaatgta ctgcctgtat cataataaaa 11460 cttgaaaatt ttatgcaaca aaaagtgtga agatatttaa cgaaaaaaaa ggtagatctt 11520 gaatgtgttg tagcacgaat aaattgctgt acttcattaa gcttcattgc caattagcta 11580 ggaattgtta agcacattgc agattgttct tggagaattc tggagttgtt atgaacatga 11640 ataccaacgg aaaaccttaa ctgaatctaa aagaaaacta ttttgaagat ggtggtgagc 11700 tgcaaaatag ctggatggat ttgaatgatt gggatgatac atcattgaac tgcactttat 11760 ataaccaaag cttagcagtt tgttagataa gagtctatgt atgtctctgg ttaggatgaa 11820 gttaatttta tgtttttaac atggtatttt tgaaggagct aatgaaacac tggacatata 11880 attggtttaa acataagggg aattaagtct ttgtagtctg tcattttttt aagtggatcc 11940 tcttggatgc gttattttct catcagctgg ctctgatcat gaatttgttg taattttatg 12000 ttgtactcag tgcatttaag aaatggtaga gtattttaat cctattactt gactaagagt 12060 gtgaaggtag tactttttag agtgcactga gtgcacttta catctttatt taaatttttt 12120 tttaacatct tatgtttaca ggcttcctgt ttgatgaaga tagcaacgga aaactcaaaa 12180 tggtggcagt tcttattacc agttgttagt attgtttctg gaaactgctt gccaagacaa 12240 catttattaa ctgttagaac acttgcttta tgtttgtgtg tacatatttt ccacaaatgt 12300 tataatttat atagtgtggt tgaacaggat gcaatctttt gttgtctaaa ggtgctgcag 12360 ttaaaaaaaa aacaaccttt tctttcaata tggcatgtag tggagttttt ttaactttaa 12420 aaacatcaaa aattgttaaa atcattgtgt tatctagtag tttataatta tcggcttata 12480 tttccccatg aatgatcaga actgacattt aattcatgtt tgtctcgcca tgcttcttta 12540 ctttaacata tttcttttgc agaatgtaaa aggtaatgat aattagttta tataagtgta 12600 ctggctgtaa atgatgctaa atatacttta tgcaattaag ggcttacaga acatgttgaa 12660 acttttttta cttttattgg gaataaggaa tgtttgcacc tccacatttt attgctt 12717 <210> SEQ ID NO 14 <211> LENGTH: 12717 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 14 atgaatacat tctggcctgg cagagaattg attgttcaat ggtatccatt tgatgaaaac 60 agaaatcacc catctgtttc atggcttaag atggtttgga aaaatcttta tatacatttt 120 tcagaggatt tgactttatt tgatgagatg ccacttatcc ccagaactat actagaggaa 180 ggtcagacat gtgtggaact cattagactc aggattccat cgttagtcat tttagacgat 240 gaatctgaag cacagcttcc agaattttta gcagacattg tacaaaaact tggagggttt 300 gtccttaaaa aattagatgc atctatacaa catccgctta ttaaaaaata tattcattca 360 ccattaccaa gtgctgtttt gcagataatg gagaagatgc cattgcagaa attgtgtaat 420 caaataactt cgctacttcc aacacacaaa gatgccctga ggaagttctt ggctagttta 480 accgatagca gtgagaaaga gaaaagaatt attcaagaat tggcaatatt caagcgcatt 540 aaccattctt ctgatcaggg aatttcctct tatacaaaat tgaaaggttg taaagtctta 600 caccatactg ccaaactccc agcagatctg cgactttcta tttcagtaat agacagtagt 660 gatgaagcta ctattcgtct ggcaaacatg ttgaaaatag aacagttaaa gaccactagc 720 tgcttaaagc ttgttttaaa agatattgaa aatgcatttt attcacatga agaggtaaca 780 cagcttatgt tatgggtcct tgagaatcta tcttctctta aaaatgagaa tccaaatgtg 840 cttgagtggt taacaccatt aaaattcatc cagatatcac aggaacagat ggtatcagct 900 ggtgaactct ttgaccctga tatagaagta ctaaaggatc tcttttgtaa tgaagaagga 960 acctatttcc caccctcagt ttttacctca ccagatattc ttcactcctt aagacagatt 1020 ggtttaaaaa acgaagccag tctcaaagaa aaggatgttg tgcaagtggc aaaaaaaatt 1080 gaagccttac aggtcggtgc ttgtcctgat caagatgttc ttctgaagaa agccaaaacc 1140 ctcttactgg ttttaaataa gaatcacaca ctgttgcaat catctgaagg aaagatgaca 1200 ttgaagaaaa taaaatgggt tccagcctgc aaggaaaggc ctccaaatta tccaggctct 1260 ttggtctgga aaggagatct ctgtaatctc tgtgcaccac cagatatgtg tgatgtaggc 1320 catgcaattc tcattggctc ctcacttcct cttgttgaaa gtatccatgt aaacctggaa 1380 aaagcattag ggatcttcac aaaacctagc cttagtgctg tcttaaaaca ctttaaaatt 1440 gttgttgatt ggtattcttc aaaaaccttt agtgatgaag actactatca attccagcat 1500 attttgcttg agatttacgg attcatgcat gatcatctaa atgaagggaa agattctttt 1560 agagccttaa aatttccatg ggtttggact ggcaaaaagt tttgtccact tgcccaggct 1620 gtgattaaac caatccatga tcttgacctt cagccttatt tgcataatgt acctaaaacc 1680 atggcaaaat tccaccaact atttaaggtc tgtggttcaa tagaggagtt gacatcagat 1740 catatttcca tggttattca gaagatatat ctcaaaagtg accaagatct cagtgaacaa 1800 gaaagcaaac aaaatcttca tcttatgttg aatattatca gatggctgta tagcaatcag 1860 attccagcaa gccccaacac accagttcct atacatcata gcaaaaatcc ttctaaactt 1920 atcatgaagc caattcacga atgctgttat tgtgacatta aagttgatga ccttaatgac 1980 ttacttgaag attctgtgga accaatcatt ttggtgcatg aggacatacc catgaaaact 2040 gcagaatggc taaaagttcc atgccttagt acaagactga taaatcctga aaacatggga 2100 tttgagcagt caggacaaag agagccactt actgtaagaa ttaaaaatat tctggaagaa 2160 tacccttcag tgtcagatat ttttaaagaa ctacttcaaa acgctgatga tgcaaatgca 2220 acagaatgca gtttcttgat tgatatgaga agaaatatgg acataagaga gaatctccta 2280 gacccaggga tggcagcttg tcatggacct gctttgtggt cattcaacaa ttctcaattc 2340 tcagattcag attttgtgaa cataactagg ttaggagaat ctttaaaaag gggagaagtt 2400 gacaaagttg gaaaatttgg tcttggattt aattctgtgt accatatcac tgacattccc 2460 atcattatga gtcgggaatt catgataatg ttcgatccaa acataaatca tatcagtaaa 2520 cacattaaag acaaatccaa tcctgggatc aaaattaatt ggagtaaaca acagaaaaga 2580 cttagaaaat ttcctaatca gttcaaacca tttatagatg tatttggctg tcagttacct 2640 ttgactgtag aagcacctta cagctataat ggaacccttt tccgactgtc ctttagaact 2700 caacaggaag caaaagtgag tgaagttagt agtacgtgct acaatacagc agatatttat 2760 tctcttgtgg atgaatttag tctctgtgga cacaggctta tcattttcac tcagagtgta 2820 aagtcaatgt atttgaagta cttgaaaatt gaggaaacca accccagttt agcacaagat 2880 acagtaataa ttaaaaaaaa atcctgctct tccaaagcat tgaacacacc tgtcttaagt 2940 gttttaaaag aggctgctaa gctcatgaag acttgcagca gcagtaataa aaagcttccc 3000 agtgatgaac caaagtcatc ttgcattctt cagatcacag tggaagaatt tcaccatgtg 3060 ttcagaagga ttgctgattt acagtcgcca ctttttagag gtccagatga tgacccagct 3120 gctctctttg aaatggctaa gtctggccaa tcaaaaaagc catcagatga gttgtcacag 3180 aaaacagtag agtgtaccac gtggcttctg tgtacttgca tggacacagg agaggctctg 3240 aagttttccc tgagtgagag tggaagaaga ctaggactgg ttccatgtgg ggcagtagga 3300 gttcagctgt cagaaatcca ggaccagaag tggacagtga aaccacacat tggagaggtg 3360 ttttgctatt tacctttacg aataaaaaca ggcttgccag ttcatatcaa tgggtgcttt 3420 gctgttacat caaataggaa agaaatctgg aaaacagata caaaaggacg atggaatacc 3480 acgttcatga gacatgttat tgtgaaagct tacttacagg tactgagtgt cttacgggac 3540 ctggccacta gtggggagct aatggattat acttactatg cagtatggcc cgatcctgat 3600 ttagttcatg atgatttttc tgtaatttgc caaggatttt atgaagatat agctcatgga 3660 aaagggaaag aactgaccaa agtcttctct gatggatcta cttgggtttc catgaagaac 3720 gtaagatttc tagatgactc tatacttaaa agaagagatg ttggttcagc agccttcaag 3780 atatttttga aatacctcaa gaagactggg tccaaaaacc tttgtgctgt tgaacttcct 3840 tcttcggtaa aattaggatt tgaagaagct ggctgcaaac agatactact tgaaaacaca 3900 ttttcagaga aacagttttt ttctgaagtg ttttttccaa atattcaaga aattgaagca 3960 gaacttagag atcctttaat gatctttgtt ctaaatgaaa aagttgatga gttctcggga 4020 gttcttcgtg ttactccatg tattccttgt tccttggagg ggcatccttt ggttttgcca 4080 tcaagattga tccaccccga aggacgagtt gcaaagttat ttgatattaa agatgggaga 4140 ttcccttatg gttctactca ggattatctc aatcctatta ttttgattaa actagttcag 4200 ttaggtatgg caaaagatga tattttatgg gatgatatgc tagaacgtgc agtgtcagta 4260 gctgaaatta ataaaagtga tcatgttgct gcatgcctaa gaagtagtat cttattgagt 4320 cttatcgatg agaaactaaa aataagggat cctagagcaa aggattttgc tgcaaaatat 4380 caaacaatcc gcttccttcc atttctgaca aaaccagcag gtttttcttt ggactggaaa 4440 ggcaacagtt ttaagcctga aaccatgttt gcagcaactg acctttatac agctgaacat 4500 caagatatag tttgtctttt gcaaccaatt ctaaatgaaa attcccattc ttttagaggt 4560 tgtggttcag tgtcattggc tgttaaagag tttttgggat tactcaagaa gccaacagtt 4620 gatctggtta taaaccaatt gaaagaagta gcaaaatcag ttgatgatgg aattacactg 4680 taccaggaga atatcaccaa tgcttgctac aaataccttc atgaagcctt gatgcaaaat 4740 gaaatcacta agatgtcaat tattgataag ttaaaaccct ttagcttcat tctagttgag 4800 aatgcatatg ttgactcaga aaaggtttct tttcatttaa attttgaggc ggcaccatac 4860 ctttatcagt tgcctaataa gtataaaaat aatttccgcg aactttttga aaccgtgggt 4920 gtgaggcagt catgcactgt tgaagatttt gctcttgttt tggaatctat tgatcaagaa 4980 agaggaacaa agcaaataac agaagagaat tttcagcttt gccgacgaat aatcagtgaa 5040 ggaatatgga gtctcattag agaaaagaaa caagaatttt gtgagaaaaa ttatggcaag 5100 atattattgc cagatactaa tcttatgctt ctccctgcta aatcgttatg ctacaatgat 5160 tgcccttgga taaaagtaaa ggataccact gtaaaatatt gtcatgctga catacccagg 5220 gaagtagcag taaaactagg agcagtccca aagcgacaca aagccttaga aagatatgca 5280 tccaatgtct gttttacaac acttggcaca gaatttgggc agaaagaaaa attgaccagc 5340 agaattaaga gcatccttaa tgcatatcct tctgaaaagg aaatgttgaa agagcttctt 5400 caaaatgctg atgatgcaaa ggcgacagaa atctgttttg tgtttgatcc tagacagcat 5460 ccagttgata gaatatttga tgataagtgg gccccattgc aagggccagc actttgtgtg 5520 tacaacaacc agccatttac agaagatgat gttagaggaa ttcagaatct tggaaaaggc 5580 acgaaagagg gaaatcctta taaaactgga cagtatggaa taggattcaa ttctgtgtat 5640 catatcacag actgcccatc ttttatttct ggcaatgaca tcctgtgtat ttttgatcct 5700 catgccagat atgcaccagg ggccacatcc attagtcccg gacgcatgtt tagagatttg 5760 gatgcagatt ttaggacaca gttctcagat gttctggatc tttatctggg aacccatttt 5820 aaactggata attgcacaat gttcagattt cctcttcgta atgcagaaat ggcaaaagtt 5880 tcggaaattt cgtctgttcc agcatcagac agaatggtcc agaatctttt ggacaaactg 5940 cgctcagatg gggcagaact tctaatgttt cttaatcaca tggaaaaaat ttctatttgt 6000 gaaatagata agagtactgg agctctaaat gtgctgtatt cagtaaaggg caaaatcaca 6060 gatggagaca gattgaaaag gaaacaattt catgcatctg taattgatag tgttactaaa 6120 aagaggcagc tcaaagacat accagttcaa caaataacct atactatgga tactgaggac 6180 tctgaaggaa atcttactac gtggctaatt tgtaatagat caggcttttc aagtatggag 6240 aaagtatcta aaagtgtcat atcagctcac aagaaccaag atattactct tttcccacgt 6300 ggtggagtag ctgcctgcat tactcacaac tataaaaaac cccatagggc cttctgtttt 6360 ttgcctcttt ctttggagac tgggctgcca tttcatgtga atggccactt tgcactggat 6420 tcagccagaa ggaacctgtg gcgtgatgat aatggagttg gtgttcgaag tgactggaat 6480 aacagtttaa tgacagcatt aatagctcct gcatatgttg aattgctaat acagttaaaa 6540 aaacggtatt tccctggttc tgatccaaca ttatcagtgt tacagaacac ccctattcat 6600 gttgtaaagg acactttaaa gaagttttta tcgtttttcc cagttaaccg tcttgatcta 6660 cagccagatt tatattgtct agtgaaagca ctttacaatt gcattcacga agacatgaaa 6720 cgtcttttac ctgttgtgcg ggctccaaat attgatggct ctgacttgca ctctgcagtt 6780 ataattactt ggatcaatat gtctacttct aataaaacta gaccattttt tgacaattta 6840 ctacaggatg aattacaaca ccttaaaaat gcagattata atatcaccac acgcaaaaca 6900 gtagcagaga atgtctatag gctgaaacat ctccttttag aaattggttt caacttggtt 6960 tataactgtg atgaaactgc taatctttac cactgtctta tagatgcaga tattcctgtt 7020 agttatgtga cccctgctga tatcagatct tttttaatga cattttcctc tcctgacact 7080 aattgccata ttgggaagct gccttgtcgt ctgcagcaga ctaatctaaa actttttcat 7140 agtttaaaac ttttagttga ttattgtttt aaagatgcag aagaaaatga gattgaagtt 7200 gagggattgc cccttctcat cacactggac agtgttttgc aaacttttga tgcaaaacga 7260 cccaagtttc taacaacata tcatgaattg attccatccc gcaaagactt gtttatgaat 7320 acattatatt tgaaatatag taatatttta ttgaactgta aagttgcaaa agtgtttgac 7380 atttccagct ttgctgattt gttatcctct gtgttgcctc gagaatataa gaccaaaagt 7440 tgcacaaagt ggaaagacaa ttttgcaagt gagtcttggc ttaagaatgc atggcatttt 7500 attagtgaat ctgtaagtgt gaaagaagat caggaagaaa caaaaccaac atttgacatt 7560 gttgttgata ctctaaaaga ctgggcattg cttccaggaa caaagtttac tgtttcagcc 7620 aaccagcttg tggttcctga aggagatgtt ctgcttcctc tcagccttat gcacattgca 7680 gtttttccaa atgcccagag tgataaagtt tttcatgctc taatgaaagc cggctgtatt 7740 cagcttgctt tgaacaaaat ctgttccaaa gacagtgcat ttgttccttt gttgtcatgt 7800 cacacagcaa atatagagag ccccacaagc atcttgaagg ctctacatta tatggtccaa 7860 acttcaacat ttagagcaga aaaattagta gaaaatgatt ttgaggcact tttgatgtat 7920 ttcaactgca atttgaatca tttgatgtcc caagatgata taaaaattct aaagtcactt 7980 ccgtgctata aatccatcag tggccgctat gtaagcattg gaaaatttgg aacatgctac 8040 gtacttacaa aaagtatccc ttcagctgaa gtggagaaat ggacacaatc atcatcatct 8100 gcatttcttg aagaaaaaat acacttaaaa gaactatatg aggtgattgg ttgtgtacct 8160 gtagatgatc ttgaggtata tttgaaacac ctcttaccaa aaattgaaaa tctctcttat 8220 gatgcaaaat tagagcactt gatctacctt aagaatagat tatcaagtgc tgaggaatta 8280 tcagagatta aggaacaact ttttgaaaaa ctggaaagtt tattgataat ccatgatgct 8340 aacagtagac taaagcaagc aaagcatttc tatgatagaa ctgtgagagt ttttgaagtt 8400 atgcttcctg aaaaattgtt tattcctaat gatttcttta agaaattgga acaacttata 8460 aaacccaaaa atcatgttac atttatgaca tcctgggtgg aattcttaag aaatattgga 8520 ctaaaataca tactttctca gcagcagttg ttacagtttg ctaaggaaat cagtgtgagg 8580 gctaatacag aaaactggtc caaagaaaca ttgcaaaata cagttgatat ccttctgcat 8640 catatattcc aagaacgaat ggatttgtta tctggaaatt ttctgaaaga actatcttta 8700 ataccattct tatgtcctga gcgggccccc gcggaattca ttagatttca tcctcaatat 8760 caagaggtaa atggaacact tcctcttata aagttcaatg gagcacaggt aaatccaaaa 8820 ttcaagcaat gtgatgtact ccagctgtta tggacatcct gccctattct tccagagaaa 8880 gctacaccct taagcattaa agaacaagaa ggtagtgacc ttggtccaca agaacagctt 8940 gaacaagttt taaatatgct taatgttaac ctggatcctc ctcttgataa ggtaatcaat 9000 aactgcagaa acatatgcaa cataacgacg ttggatgaag aaatggtaaa aactagagca 9060 aaagtcttaa ggagcatata tgaattcctc agtgcagaaa aaagggaatt tcgttttcag 9120 ttgcgagggg ttgcttttgt gatggtagaa gatggttgga aacttctgaa gcctgaggag 9180 gtagtcataa acctagaata tgaatctgat tttaaacctt atttgtacaa gctaccttta 9240 gaacttggca catttcacca gttgttcaaa cacttaggta ctgaagatat tatttcaact 9300 aagcaatatg ttgaagtgtt gagccgcata tttaaaaatt ctgagggcaa acaattagat 9360 cctaatgaaa tgcgtacagt taagagagta gtttctggtc tgttcaggag tctacagaat 9420 gattcagtca aggtgaggag tgatctcgag aatgtacgag accttgcgct ttacctccca 9480 agccaggatg gtagattggt aaagtcaagc atcttagtgt ttgacgatgc gccacattat 9540 aaaagtagaa tccaggggaa tattggtgtg caaatgttag ttgatctcag ccagtgctac 9600 ttagggaaag accatggatt tcacactaag ttgataatgc tctttcctca aaaacttaga 9660 cctcgattat tgagcagtat acttgaagaa caattagatg aagagactcc caaagtttgt 9720 cagtttggag cgttgtgttc tcttcaagga agattgcagt tactcttgtc ttctgaacag 9780 ttcattacag gactgattag aattatgaag catgaaaatg ataatgcttt tctggccaat 9840 gaagaaaaag ccataagact ttgcaaagcc ctaagagaag gattgaaagt atcctgcttt 9900 gaaaagcttc aaacaacatt aagagttaaa ggttttaatc ctattcccca cagcagaagt 9960 gaaacttttg cttttttgaa gcgatttggt aatgcagtca tcttgctcta cattcaacat 10020 tcagacagta aagacattaa tttcctgtta gcattggcaa tgactcttaa atcagcaact 10080 gacaatttga tttctgacac ttcatattta attgctatgc taggatgcaa tgatatttac 10140 aggattggtg agaaacttga cagtttagga gtgaaatatg actcttcgga gccatcaaaa 10200 ctggaacttc caatgcctgg cacaccaatt cctgctgaaa ttcattacac tctgcttatg 10260 gacccaatga atgtttttta cccgggagaa tatgttgggt accttgttga tgctgaaggt 10320 ggtgatatct atggatcata ccagccaaca tacacatatg caattattgt acaagaagtt 10380 gaaagagaag atgctgacaa ttctagtttt ctaggaaaga tatatcagat agatattggt 10440 tatagtgaat ataaaatagt tagctctctt gatctgtata agttttcaag acctgaggaa 10500 agctctcaaa gcagggacag tgctccttct acaccaacca gccccactga gttcctcacc 10560 cctggcctga gaagcattcc tcctcttttc tctggtagag agagccacaa gacttcttcc 10620 aaacatcagt cccccaaaaa gcttaaggtt aattctttac cagaaatctt aaaagaagtg 10680 acatctgtgg tggagcaagc atggaagctt ccagaatcgg aacgaaaaaa gattattagg 10740 cggttgtatt tgaaatggca tcctgacaaa aatccagaga accatgacat tgccaatgaa 10800 gtttttaaac atttgcagaa tgaaatcaac agattagaaa aacaggcttt tctagatcaa 10860 aatgcagaca gggcctccag acgaacattt tcaacctcag catcccgatt tcagtcagac 10920 aaatactcat ttcagagatt ctatacttca tggaatcaag aagcaacgag ccataaatct 10980 gaaagacagc aacagaacaa agaaaaatgc cccccttcag ccggacagac ttactctcaa 11040 aggttctttg ttcctcccac tttcaagtcg gttggcaatc cagtggaagc acgcagatgg 11100 ctaagacaag ccagagcaaa cttctcagct gccaggaatg accttcataa aaatgccaat 11160 gagtgggtgt gctttaaatg ttacctttct accaagttag ctttgattgc agctgactat 11220 gctgtgaggg gaaagtctga taaagatgta aaaccaactg cacttgctca gaaaatagag 11280 gaatatagtc agcaacttga aggactgaca aatgatgttc acacattgga agcttatggt 11340 gtagacagtt taaaaacaag ataccctgat ttgcttccct ttcctcagat cccaaatgac 11400 aggttcactt ctgaggttgc tatgagggtg atggaatgta ctgcctgtat cataataaaa 11460 cttgaaaatt ttatgcaaca aaaagtgtga agatatttaa cgaaaaaaaa ggtagatctt 11520 gaatgtgttg tagcacgaat aaattgctgt acttcattaa gcttcattgc caattagcta 11580 ggaattgtta agcacattgc agattgttct tggagaattc tggagttgtt atgaacatga 11640 ataccaacgg aaaaccttaa ctgaatctaa aagaaaacta ttttgaagat ggtggtgagc 11700 tgcaaaatag ctggatggat ttgaatgatt gggatgatac atcattgaac tgcactttat 11760 ataaccaaag cttagcagtt tgttagataa gagtctatgt atgtctctgg ttaggatgaa 11820 gttaatttta tgtttttaac atggtatttt tgaaggagct aatgaaacac tggacatata 11880 attggtttaa acataagggg aattaagtct ttgtagtctg tcattttttt aagtggatcc 11940 tcttggatgc gttattttct catcagctgg ctctgatcat gaatttgttg taattttatg 12000 ttgtactcag tgcatttaag aaatggtaga gtattttaat cctattactt gactaagagt 12060 gtgaaggtag tactttttag agtgcactga gtgcacttta catctttatt taaatttttt 12120 tttaacatct tatgtttaca ggcttcctgt ttgatgaaga tagcaacgga aaactcaaaa 12180 tggtggcagt tcttattacc agttgttagt attgtttctg gaaactgctt gccaagacaa 12240 catttattaa ctgttagaac acttgcttta tgtttgtgtg tacatatttt ccacaaatgt 12300 tataatttat atagtgtggt tgaacaggat gcaatctttt gttgtctaaa ggtgctgcag 12360 ttaaaaaaaa aacaaccttt tctttcaata tggcatgtag tggagttttt ttaactttaa 12420 aaacatcaaa aattgttaaa atcattgtgt tatctagtag tttataatta tcggcttata 12480 tttccccatg aatgatcaga actgacattt aattcatgtt tgtctcgcca tgcttcttta 12540 ctttaacata tttcttttgc agaatgtaaa aggtaatgat aattagttta tataagtgta 12600 ctggctgtaa atgatgctaa atatacttta tgcaattaag ggcttacaga acatgttgaa 12660 acttttttta cttttattgg gaataaggaa tgtttgcacc tccacatttt attgctt 12717 <210> SEQ ID NO 15 <211> LENGTH: 12793 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 15 atgatttaca ggaagaccat gtactcagct gcagcttcta aatccagaac gatttgcacg 60 tcttatcaag gaagtaatga atacattctg gcctggcaga gaattgattg ttcaatggta 120 tccatttgat gaaaacagaa atcacccatc tgtttcatgg cttaagatgg tttggaaaaa 180 tctttatata catttttcag aggatttgac tttatttgat gagatgccac ttatccccag 240 aactatacta gaggaaggtc agacatgtgt ggaactcatt agactcagga ttccatcgtt 300 agtcatttta gacgatgaat ctgaagcaca gcttccagaa tttttagcag acattgtaca 360 aaaacttgga gggtttgtcc ttaaaaaatt agatgcatct atacaacatc cgcttattaa 420 aaaatatatt cattcaccat taccaagtgc tgttttgcag ataatggaga agatgccatt 480 gcagaaattg tgtaatcaaa taacttcgct acttccaaca cacaaagatg ccctgaggaa 540 gttcttggct agtttaaccg atagcagtga gaaagagaaa agaattattc aagaattggc 600 aatattcaag cgcattaacc attcttctga tcagggaatt tcctcttata caaaattgaa 660 aggttgtaaa gtcttacacc atactgccaa actcccagca gatctgcgac tttctatttc 720 agtaatagac agtagtgatg aagctactat tcgtctggca aacatgttga aaatagaaca 780 gttaaagacc actagctgct taaagcttgt tttaaaagat attgaaaatg cattttattc 840 acatgaagag gtaacacagc ttatgttatg ggtccttgag aatctatctt ctcttaaaaa 900 tgagaatcca aatgtgcttg agtggttaac accattaaaa ttcatccaga tatcacagga 960 acagatggta tcagctggtg aactctttga ccctgatata gaagtactaa aggatctctt 1020 ttgtaatgaa gaaggaacct atttcccacc ctcagttttt acctcaccag atattcttca 1080 ctccttaaga cagattggtt taaaaaacga agccagtctc aaagaaaagg atgttgtgca 1140 agtggcaaaa aaaattgaag ccttacaggt cggtgcttgt cctgatcaag atgttcttct 1200 gaagaaagcc aaaaccctct tactggtttt aaataagaat cacacactgt tgcaatcatc 1260 tgaaggaaag atgacattga agaaaataaa atgggttcca gcctgcaagg aaaggcctcc 1320 aaattatcca ggctctttgg tctggaaagg agatctctgt aatctctgtg caccaccaga 1380 tatgtgtgat gtaggccatg caattctcat tggctcctca cttcctcttg ttgaaagtat 1440 ccatgtaaac ctggaaaaag cattagggat cttcacaaaa cctagcctta gtgctgtctt 1500 aaaacacttt aaaattgttg ttgattggta ttcttcaaaa acctttagtg atgaagacta 1560 ctatcaattc cagcatattt tgcttgagat ttacggattc atgcatgatc atctaaatga 1620 agggaaagat tcttttagag ccttaaaatt tccatgggtt tggactggca aaaagttttg 1680 tccacttgcc caggctgtga ttaaaccaat ccatgatctt gaccttcagc cttatttgca 1740 taatgtacct aaaaccatgg caaaattcca ccaactattt aaggtctgtg gttcaataga 1800 ggagttgaca tcagatcata tttccatggt tattcagaag atatatctca aaagtgacca 1860 agatctcagt gaacaagaaa gcaaacaaaa tcttcatctt atgttgaata ttatcagatg 1920 gctgtatagc aatcagattc cagcaagccc caacacacca gttcctatac atcatagcaa 1980 aaatccttct aaacttatca tgaagccaat tcacgaatgc tgttattgtg acattaaagt 2040 tgatgacctt aatgacttac ttgaagattc tgtggaacca atcattttgg tgcatgagga 2100 catacccatg aaaactgcag aatggctaaa agttccatgc cttagtacaa gactgataaa 2160 tcctgaaaac atgggatttg agcagtcagg acaaagagag ccacttactg taagaattaa 2220 aaatattctg gaagaatacc cttcagtgtc agatattttt aaagaactac ttcaaaacgc 2280 tgatgatgca aatgcaacag aatgcagttt cttgattgat atgagaagaa atatggacat 2340 aagagagaat ctcctagacc cagggatggc agcttgtcat ggacctgctt tgtggtcatt 2400 caacaattct caattctcag attcagattt tgtgaacata actaggttag gagaatcttt 2460 aaaaagggga gaagttgaca aagttggaaa atttggtctt ggatttaatt ctgtgtacca 2520 tatcactgac attcccatca ttatgagtcg ggaattcatg ataatgttcg atccaaacat 2580 aaatcatatc agtaaacaca ttaaagacaa atccaatcct gggatcaaaa ttaattggag 2640 taaacaacag aaaagactta gaaaatttcc taatcagttc aaaccattta tagatgtatt 2700 tggctgtcag ttacctttga ctgtagaagc accttacagc tataatggaa cccttttccg 2760 actgtccttt agaactcaac aggaagcaaa agtgagtgaa gttagtagta cgtgctacaa 2820 tacagcagat atttattctc ttgtggatga atttagtctc tgtggacaca ggcttatcat 2880 tttcactcag agtgtaaagt caatgtattt gaagtacttg aaaattgagg aaaccaaccc 2940 cagtttagca caagatacag taataattaa aaaaaaatcc tgctcttcca aagcattgaa 3000 cacacctgtc ttaagtgttt taaaagaggc tgctaagctc atgaagactt gcagcagcag 3060 taataaaaag cttcccagtg atgaaccaaa gtcatcttgc attcttcaga tcacagtgga 3120 agaatttcac catgtgttca gaaggattgc tgatttacag tcgccacttt ttagaggtcc 3180 agatgatgac ccagctgctc tctttgaaat ggctaagtct ggccaatcaa aaaagccatc 3240 agatgagttg tcacagaaaa cagtagagtg taccacgtgg cttctgtgta cttgcatgga 3300 cacaggagag gctctgaagt tttccctgag tgagagtgga agaagactag gactggttcc 3360 atgtggggca gtaggagttc agctgtcaga aatccaggac cagaagtgga cagtgaaacc 3420 acacattgga gaggtgtttt gctatttacc tttacgaata aaaacaggct tgccagttca 3480 tatcaatggg tgctttgctg ttacatcaaa taggaaagaa atctggaaaa cagatacaaa 3540 aggacgatgg aataccacgt tcatgagaca tgttattgtg aaagcttact tacaggtact 3600 gagtgtctta cgggacctgg ccactagtgg ggagctaatg gattatactt actatgcagt 3660 atggcccgat cctgatttag ttcatgatga tttttctgta atttgccaag gattttatga 3720 agatatagct catggaaaag ggaaagaact gaccaaagtc ttctctgatg gatctacttg 3780 ggtttccatg aagaacgtaa gatttctaga tgactctata cttaaaagaa gagatgttgg 3840 ttcagcagcc ttcaagatat ttttgaaata cctcaagaag actgggtcca aaaacctttg 3900 tgctgttgaa cttccttctt cggtaaaatt aggatttgaa gaagctggct gcaaacagat 3960 actacttgaa aacacatttt cagagaaaca gtttttttct gaagtgtttt ttccaaatat 4020 tcaagaaatt gaagcagaac ttagagatcc tttaatgatc tttgttctaa atgaaaaagt 4080 tgatgagttc tcgggagttc ttcgtgttac tccatgtatt ccttgttcct tggaggggca 4140 tcctttggtt ttgccatcaa gattgatcca ccccgaagga cgagttgcaa agttatttga 4200 tattaaagat gggagattcc cttatggttc tactcaggat tatctcaatc ctattatttt 4260 gattaaacta gttcagttag gtatggcaaa agatgatatt ttatgggatg atatgctaga 4320 acgtgcagtg tcagtagctg aaattaataa aagtgatcat gttgctgcat gcctaagaag 4380 tagtatctta ttgagtctta tcgatgagaa actaaaaata agggatccta gagcaaagga 4440 ttttgctgca aaatatcaaa caatccgctt ccttccattt ctgacaaaac cagcaggttt 4500 ttctttggac tggaaaggca acagttttaa gcctgaaacc atgtttgcag caactgacct 4560 ttatacagct gaacatcaag atatagtttg tcttttgcaa ccaattctaa atgaaaattc 4620 ccattctttt agaggttgtg gttcagtgtc attggctgtt aaagagtttt tgggattact 4680 caagaagcca acagttgatc tggttataaa ccaattgaaa gaagtagcaa aatcagttga 4740 tgatggaatt acactgtacc aggagaatat caccaatgct tgctacaaat accttcatga 4800 agccttgatg caaaatgaaa tcactaagat gtcaattatt gataagttaa aaccctttag 4860 cttcattcta gttgagaatg catatgttga ctcagaaaag gtttcttttc atttaaattt 4920 tgaggcggca ccataccttt atcagttgcc taataagtat aaaaataatt tccgcgaact 4980 ttttgaaacc gtgggtgtga ggcagtcatg cactgttgaa gattttgctc ttgttttgga 5040 atctattgat caagaaagag gaacaaagca aataacagaa gagaattttc agctttgccg 5100 acgaataatc agtgaaggaa tatggagtct cattagagaa aagaaacaag aattttgtga 5160 gaaaaattat ggcaagatat tattgccaga tactaatctt atgcttctcc ctgctaaatc 5220 gttatgctac aatgattgcc cttggataaa agtaaaggat accactgtaa aatattgtca 5280 tgctgacata cccagggaag tagcagtaaa actaggagca gtcccaaagc gacacaaagc 5340 cttagaaaga tatgcatcca atgtctgttt tacaacactt ggcacagaat ttgggcagaa 5400 agaaaaattg accagcagaa ttaagagcat ccttaatgca tatccttctg aaaaggaaat 5460 gttgaaagag cttcttcaaa atgctgatga tgcaaaggcg acagaaatct gttttgtgtt 5520 tgatcctaga cagcatccag ttgatagaat atttgatgat aagtgggccc cattgcaagg 5580 gccagcactt tgtgtgtaca acaaccagcc atttacagaa gatgatgtta gaggaattca 5640 gaatcttgga aaaggcacga aagagggaaa tccttataaa actggacagt atggaatagg 5700 attcaattct gtgtatcata tcacagactg cccatctttt atttctggca atgacatcct 5760 gtgtattttt gatcctcatg ccagatatgc accaggggcc acatccatta gtcccggacg 5820 catgtttaga gatttggatg cagattttag gacacagttc tcagatgttc tggatcttta 5880 tctgggaacc cattttaaac tggataattg cacaatgttc agatttcctc ttcgtaatgc 5940 agaaatggca aaagtttcgg aaatttcgtc tgttccagca tcagacagaa tggtccagaa 6000 tcttttggac aaactgcgct cagatggggc agaacttcta atgtttctta atcacatgga 6060 aaaaatttct atttgtgaaa tagataagag tactggagct ctaaatgtgc tgtattcagt 6120 aaagggcaaa atcacagatg gagacagatt gaaaaggaaa caatttcatg catctgtaat 6180 tgatagtgtt actaaaaaga ggcagctcaa agacatacca gttcaacaaa taacctatac 6240 tatggatact gaggactctg aaggaaatct tactacgtgg ctaatttgta atagatcagg 6300 cttttcaagt atggagaaag tatctaaaag tgtcatatca gctcacaaga accaagatat 6360 tactcttttc ccacgtggtg gagtagctgc ctgcattact cacaactata aaaaacccca 6420 tagggccttc tgttttttgc ctctttcttt ggagactggg ctgccatttc atgtgaatgg 6480 ccactttgca ctggattcag ccagaaggaa cctgtggcgt gatgataatg gagttggtgt 6540 tcgaagtgac tggaataaca gtttaatgac agcattaata gctcctgcat atgttgaatt 6600 gctaatacag ttaaaaaaac ggtatttccc tggttctgat ccaacattat cagtgttaca 6660 gaacacccct attcatgttg taaaggacac tttaaagaag tttttatcgt ttttcccagt 6720 taaccgtctt gatctacagc cagatttata ttgtctagtg aaagcacttt acaattgcat 6780 tcacgaagac atgaaacgtc ttttacctgt tgtgcgggct ccaaatattg atggctctga 6840 cttgcactct gcagttataa ttacttggat caatatgtct acttctaata aaactagacc 6900 attttttgac aatttactac aggatgaatt acaacacctt aaaaatgcag attataatat 6960 caccacacgc aaaacagtag cagagaatgt ctataggctg aaacatctcc ttttagaaat 7020 tggtttcaac ttggtttata actgtgatga aactgctaat ctttaccact gtcttataga 7080 tgcagatatt cctgttagtt atgtgacccc tgctgatatc agatcttttt taatgacatt 7140 ttcctctcct gacactaatt gccatattgg gaagctgcct tgtcgtctgc agcagactaa 7200 tctaaaactt tttcatagtt taaaactttt agttgattat tgttttaaag atgcagaaga 7260 aaatgagatt gaagttgagg gattgcccct tctcatcaca ctggacagtg ttttgcaaac 7320 ttttgatgca aaacgaccca agtttctaac aacatatcat gaattgattc catcccgcaa 7380 agacttgttt atgaatacat tatatttgaa atatagtaat attttattga actgtaaagt 7440 tgcaaaagtg tttgacattt ccagctttgc tgatttgtta tcctctgtgt tgcctcgaga 7500 atataagacc aaaagttgca caaagtggaa agacaatttt gcaagtgagt cttggcttaa 7560 gaatgcatgg cattttatta gtgaatctgt aagtgtgaaa gaagatcagg aagaaacaaa 7620 accaacattt gacattgttg ttgatactct aaaagactgg gcattgcttc caggaacaaa 7680 gtttactgtt tcagccaacc agcttgtggt tcctgaagga gatgttctgc ttcctctcag 7740 ccttatgcac attgcagttt ttccaaatgc ccagagtgat aaagtttttc atgctctaat 7800 gaaagccggc tgtattcagc ttgctttgaa caaaatctgt tccaaagaca gtgcacttgt 7860 tcctttgttg tcatgtcaca cagcaaatat agagagcccc acaagcatct tgaaggctct 7920 acattatatg gtccaaactt caacatttag agcagaaaaa ttagtagaaa atgattttga 7980 ggcacttttg atgtatttca actgcaattt gaatcatttg atgtcccaag atgatataaa 8040 aattctaaag tcacttccgt gctataaatc catcagtggc cgctatgtaa gcattggaaa 8100 atttggaaca tgctacgtac ttacaaaaag tatcccttca gctgaagtgg agaaatggac 8160 acaatcatca tcatctgcat ttcttgaaga aaaaatacac ttaaaagaac tatatgaggt 8220 gattggttgt gtacctgtag atgatcttga ggtatatttg aaacacctct taccaaaaat 8280 tgaaaatctc tcttatgatg caaaattaga gcacttgatc taccttaaga atagattatc 8340 aagtgctgag gaattatcag agattaagga acaacttttt gaaaaactgg aaagtttatt 8400 gataatccat gatgctaaca gtagactaaa gcaagcaaag catttctatg atagaactgt 8460 gagagttttt gaagttatgc ttcctgaaaa attgtttatt cctaatgatt tctttaagaa 8520 attggaacaa cttataaaac ccaaaaatca tgttacattt atgacatcct gggtggaatt 8580 cttaagaaat attggactaa aatacatact ttctcagcag cagttgttac agtttgctaa 8640 ggaaatcagt gtgagggcta atacagaaaa ctggtccaaa gaaacattgc aaaatacagt 8700 tgatatcctt ctgcatcata tattccaaga acgaatggat ttgttatctg gaaattttct 8760 gaaagaacta tctttaatac cattcttatg tcctgagcgg gcccccgcgg aattcattag 8820 atttcatcct caatatcaag aggtaaatgg aacacttcct cttataaagt tcaatggagc 8880 acaggtaaat ccaaaattca agcaatgtga tgtactccag ctgttatgga catcctgccc 8940 tattcttcca gagaaagcta cacccttaag cattaaagaa caagaaggta gtgaccttgg 9000 tccacaagaa cagcttgaac aagttttaaa tatgcttaat gttaacctgg atcctcctct 9060 tgataaggta atcaataact gcagaaacat atgcaacata acgacgttgg atgaagaaat 9120 ggtaaaaact agagcaaaag tcttaaggag catatatgaa ttcctcagtg cagaaaaaag 9180 ggaatttcgt tttcagttgc gaggggttgc ttttgtgatg gtagaagatg gttggaaact 9240 tctgaagcct gaggaggtag tcataaacct agaatatgaa tctgatttta aaccttattt 9300 gtacaagcta cctttagaac ttggcacatt tcaccagttg ttcaaacact taggtactga 9360 agatattatt tcaactaagc aatatgttga agtgttgagc cgcatattta aaaattctga 9420 gggcaaacaa ttagatccta atgaaatgcg tacagttaag agagtagttt ctggtctgtt 9480 caggagtcta cagaatgatt cagtcaaggt gaggagtgat ctcgagaatg tacgagacct 9540 tgcgctttac ctcccaagcc aggatggtag attggtaaag tcaagcatct tagtgtttga 9600 cgatgcgcca cattataaaa gtagaatcca ggggaatatt ggtgtgcaaa tgttagttga 9660 tctcagccag tgctacttag ggaaagacca tggatttcac actaagttga taatgctctt 9720 tcctcaaaaa cttagacctc gattattgag cagtatactt gaagaacaat tagatgaaga 9780 gactcccaaa gtttgtcagt ttggagcgtt gtgttctctt caaggaagat tgcagttact 9840 cttgtcttct gaacagttca ttacaggact gattagaatt atgaagcatg aaaatgataa 9900 tgcttttctg gccaatgaag aaaaagccat aagactttgc aaagccctaa gagaaggatt 9960 gaaagtatcc tgctttgaaa agcttcaaac aacattaaga gttaaaggtt ttaatcctat 10020 tccccacagc agaagtgaaa cttttgcttt tttgaagcga tttggtaatg cagtcatctt 10080 gctctacatt caacattcag acagtaaaga cattaatttc ctgttagcac tggcaatgac 10140 tcttaaatca gcaactgaca atttgatttc tgacacttca tatttaattg ctatgctagg 10200 atgcaatgat atttacagga ttggtgagaa acttgacagt ttaggagtga aatatgactc 10260 ttcggagcca tcaaaactgg aacttccaat gcctggcaca ccaattcctg ctgaaattca 10320 ttacactctg cttatggacc caatgaatgt tttttacccg ggagaatatg ttgggtacct 10380 tgttgatgct gaaggtggtg atatctatgg atcataccag ccaacataca catatgcaat 10440 tattgtacaa gaagttgaaa gagaagatgc tgacaattct agttttctag gaaagatata 10500 tcagatagat attggttata gtgaatataa aatagttagc tctcttgatc tgtataagtt 10560 ttcaagacct gaggaaagct ctcaaagcag ggacagtgct ccttctacac caaccagccc 10620 cactgagttc ctcacccctg gcctgagaag cattcctcct cttttctctg gtagagagag 10680 ccacaagact tcttccaaac atcagtcccc caaaaagctt aaggttaatt ctttaccaga 10740 aatcttaaaa gaagtgacat ctgtggtgga gcaagcatgg aagcttccag aatcggaacg 10800 aaaaaagatt attaggcggt tgtatttgaa atggcatcct gacaaaaatc cagagaacca 10860 tgacattgcc aatgaagttt ttaaacattt gcagaatgaa atcaacagat tagaaaaaca 10920 ggcttttcta gatcaaaatg cagacagggc ctccagacga acattttcaa cctcagcatc 10980 ccgatttcag tcagacaaat actcatttca gagattctat acttcatgga atcaagaagc 11040 aacgagccat aaatctgaaa gacagcaaca gaacaaagaa aaatgccccc cttcagccgg 11100 acagacttac tctcaaaggt tctttgttcc tcccactttc aagtcggttg gcaatccagt 11160 ggaagcacgc agatggctaa gacaagccag agcaaacttc tcagctgcca ggaatgacct 11220 tcataaaaat gccaatgagt gggtgtgctt taaatgttac ctttctacca agttagcttt 11280 gattgcagct gactatgctg tgaggggaaa gtctgataaa gatgtaaaac caactgcact 11340 tgctcagaaa atagaggaat atagtcagca acttgaagga ctgacaaatg atgttcacac 11400 attggaagct tatggtgtag acagtttaaa aacaagatac cctgatttgc ttccctttcc 11460 tcagatccca aatgacaggt tcacttctga ggttgctatg agggtgatgg aatgtactgc 11520 ctgtatcata ataaaacttg aaaattttat gcaacaaaaa gtgtgaagat atttaacgaa 11580 aaaaaaggta gatcttgaat gtgttgtagc acgaataaat tgctgtactt cattaagctt 11640 cattgccaat tagctaggaa ttgttaagca cattgcagat tgttcttgga gaattctgga 11700 gttgttatga acatgaatac caacggaaaa ccttaactga atctaaaaga aaactatttt 11760 gaagatggtg gtgagctgca aaatagctgg atggatttga atgattggga tgatacatca 11820 ttgaactgca ctttatataa ccaaagctta gcagtttgtt agataagagt ctatgtatgt 11880 ctctggttag gatgaagtta attttatgtt tttaacatgg tatttttgaa ggagctaatg 11940 aaacactgga catataattg gtttaaacat aaggggaatt aagtctttgt agtctgtcat 12000 ttttttaagt ggatcctctt ggatgcgtta ttttctcatc agctggctct gatcatgaat 12060 ttgttgtaat tttatgttgt actcagtgca tttaagaaat ggtagagtat tttaatccta 12120 ttacttgact aagagtgtga aggtagtact ttttagagtg cactgagtgc actttacatc 12180 tttatttaaa ttttttttta acatcttatg tttacaggct tcctgtttga tgaagatagc 12240 aacggaaaac tcaaaatggt ggcagttctt attaccagtt gttagtattg tttctggaaa 12300 ctgcttgcca agacaacatt tattaactgt tagaacactt gctttatgtt tgtgtgtaca 12360 tattttccac aaatgttata atttatatag tgtggttgaa caggatgcaa tcttttgttg 12420 tctaaaggtg ctgcagttaa aaaaaaaaca accttttctt tcaatatggc atgtagtgga 12480 gtttttttaa ctttaaaaac atcaaaaatt gttaaaatca ttgtgttatc tagtagttta 12540 taattatcgg cttatatttc cccatgaatg atcagaactg acatttaatt catgtttgtc 12600 tcgccatgct tctttacttt aacatatttc ttttgcagaa tgtaaaaggt aatgataatt 12660 agtttatata agtgtactgg ctgtaaatga tgctaaatat actttatgca attaagggct 12720 tacagaacat gttgaaactt tttttacttt tattgggaat aaggaatgtt tgcacctcca 12780 cattttattg ctt 12793 <210> SEQ ID NO 16 <211> LENGTH: 3829 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 16 Met Asn Thr Phe Trp Pro Gly Arg Glu Leu Ile Val Gln Trp Tyr Pro 1 5 10 15 Phe Asp Glu Asn Arg Asn His Pro Ser Val Ser Trp Leu Lys Met Val 20 25 30 Trp Lys Asn Leu Tyr Ile His Phe Ser Glu Asp Leu Thr Leu Phe Asp 35 40 45 Glu Met Pro Leu Ile Pro Arg Thr Ile Leu Glu Glu Gly Gln Thr Cys 50 55 60 Val Glu Leu Ile Arg Leu Arg Ile Pro Ser Leu Val Ile Leu Asp Asp 65 70 75 80 Glu Ser Glu Ala Gln Leu Pro Glu Phe Leu Ala Asp Ile Val Gln Lys 85 90 95 Leu Gly Gly Phe Val Leu Lys Lys Leu Asp Ala Ser Ile Gln His Pro 100 105 110 Leu Ile Lys Lys Tyr Ile His Ser Pro Leu Pro Ser Ala Val Leu Gln 115 120 125 Ile Met Glu Lys Met Pro Leu Gln Lys Leu Cys Asn Gln Ile Thr Ser 130 135 140 Leu Leu Pro Thr His Lys Asp Ala Leu Arg Lys Phe Leu Ala Ser Leu 145 150 155 160 Thr Asp Ser Ser Glu Lys Glu Lys Arg Ile Ile Gln Glu Leu Ala Ile 165 170 175 Phe Lys Arg Ile Asn His Ser Ser Asp Gln Gly Ile Ser Ser Tyr Thr 180 185 190 Lys Leu Lys Gly Cys Lys Val Leu His His Thr Ala Lys Leu Pro Ala 195 200 205 Asp Leu Arg Leu Ser Ile Ser Val Ile Asp Ser Ser Asp Glu Ala Thr 210 215 220 Ile Arg Leu Ala Asn Met Leu Lys Ile Glu Gln Leu Lys Thr Thr Ser 225 230 235 240 Cys Leu Lys Leu Val Leu Lys Asp Ile Glu Asn Ala Phe Tyr Ser His 245 250 255 Glu Glu Val Thr Gln Leu Met Leu Trp Val Leu Glu Asn Leu Ser Ser 260 265 270 Leu Lys Asn Glu Asn Pro Asn Val Leu Glu Trp Leu Thr Pro Leu Lys 275 280 285 Phe Ile Gln Ile Ser Gln Glu Gln Met Val Ser Ala Gly Glu Leu Phe 290 295 300 Asp Pro Asp Ile Glu Val Leu Lys Asp Leu Phe Cys Asn Glu Glu Gly 305 310 315 320 Thr Tyr Phe Pro Pro Ser Val Phe Thr Ser Pro Asp Ile Leu His Ser 325 330 335 Leu Arg Gln Ile Gly Leu Lys Asn Glu Ala Ser Leu Lys Glu Lys Asp 340 345 350 Val Val Gln Val Ala Lys Lys Ile Glu Ala Leu Gln Val Gly Ala Cys 355 360 365 Pro Asp Gln Asp Val Leu Leu Lys Lys Ala Lys Thr Leu Leu Leu Val 370 375 380 Leu Asn Lys Asn His Thr Leu Leu Gln Ser Ser Glu Gly Lys Met Thr 385 390 395 400 Leu Lys Lys Ile Lys Trp Val Pro Ala Cys Lys Glu Arg Pro Pro Asn 405 410 415 Tyr Pro Gly Ser Leu Val Trp Lys Gly Asp Leu Cys Asn Leu Cys Ala 420 425 430 Pro Pro Asp Met Cys Asp Val Gly His Ala Ile Leu Ile Gly Ser Ser 435 440 445 Leu Pro Leu Val Glu Ser Ile His Val Asn Leu Glu Lys Ala Leu Gly 450 455 460 Ile Phe Thr Lys Pro Ser Leu Ser Ala Val Leu Lys His Phe Lys Ile 465 470 475 480 Val Val Asp Trp Tyr Ser Ser Lys Thr Phe Ser Asp Glu Asp Tyr Tyr 485 490 495 Gln Phe Gln His Ile Leu Leu Glu Ile Tyr Gly Phe Met His Asp His 500 505 510 Leu Asn Glu Gly Lys Asp Ser Phe Arg Ala Leu Lys Phe Pro Trp Val 515 520 525 Trp Thr Gly Lys Lys Phe Cys Pro Leu Ala Gln Ala Val Ile Lys Pro 530 535 540 Ile His Asp Leu Asp Leu Gln Pro Tyr Leu His Asn Val Pro Lys Thr 545 550 555 560 Met Ala Lys Phe His Gln Leu Phe Lys Val Cys Gly Ser Ile Glu Glu 565 570 575 Leu Thr Ser Asp His Ile Ser Met Val Ile Gln Lys Ile Tyr Leu Lys 580 585 590 Ser Asp Gln Asp Leu Ser Glu Gln Glu Ser Lys Gln Asn Leu His Leu 595 600 605 Met Leu Asn Ile Ile Arg Trp Leu Tyr Ser Asn Gln Ile Pro Ala Ser 610 615 620 Pro Asn Thr Pro Val Pro Ile His His Ser Lys Asn Pro Ser Lys Leu 625 630 635 640 Ile Met Lys Pro Ile His Glu Cys Cys Tyr Cys Asp Ile Lys Val Asp 645 650 655 Asp Leu Asn Asp Leu Leu Glu Asp Ser Val Glu Pro Ile Ile Leu Val 660 665 670 His Glu Asp Ile Pro Met Lys Thr Ala Glu Trp Leu Lys Val Pro Cys 675 680 685 Leu Ser Thr Arg Leu Ile Asn Pro Glu Asn Met Gly Phe Glu Gln Ser 690 695 700 Gly Gln Arg Glu Pro Leu Thr Val Arg Ile Lys Asn Ile Leu Glu Glu 705 710 715 720 Tyr Pro Ser Val Ser Asp Ile Phe Lys Glu Leu Leu Gln Asn Ala Asp 725 730 735 Asp Ala Asn Ala Thr Glu Cys Ser Phe Leu Ile Asp Met Arg Arg Asn 740 745 750 Met Asp Ile Arg Glu Asn Leu Leu Asp Pro Gly Met Ala Ala Cys His 755 760 765 Gly Pro Ala Leu Trp Ser Phe Asn Asn Ser Gln Phe Ser Asp Ser Asp 770 775 780 Phe Val Asn Ile Thr Arg Leu Gly Glu Ser Leu Lys Arg Gly Glu Val 785 790 795 800 Asp Lys Val Gly Lys Phe Gly Leu Gly Phe Asn Ser Val Tyr His Ile 805 810 815 Thr Asp Ile Pro Ile Ile Met Ser Arg Glu Phe Met Ile Met Phe Asp 820 825 830 Pro Asn Ile Asn His Ile Ser Lys His Ile Lys Asp Lys Ser Asn Pro 835 840 845 Gly Ile Lys Ile Asn Trp Ser Lys Gln Gln Lys Arg Leu Arg Lys Phe 850 855 860 Pro Asn Gln Phe Lys Pro Phe Ile Asp Val Phe Gly Cys Gln Leu Pro 865 870 875 880 Leu Thr Val Glu Ala Pro Tyr Ser Tyr Asn Gly Thr Leu Phe Arg Leu 885 890 895 Ser Phe Arg Thr Gln Gln Glu Ala Lys Val Ser Glu Val Ser Ser Thr 900 905 910 Cys Tyr Asn Thr Ala Asp Ile Tyr Ser Leu Val Asp Glu Phe Ser Leu 915 920 925 Cys Gly His Arg Leu Ile Ile Phe Thr Gln Ser Val Lys Ser Met Tyr 930 935 940 Leu Lys Tyr Leu Lys Ile Glu Glu Thr Asn Pro Ser Leu Ala Gln Asp 945 950 955 960 Thr Val Ile Ile Lys Lys Lys Ser Cys Ser Ser Lys Ala Leu Asn Thr 965 970 975 Pro Val Leu Ser Val Leu Lys Glu Ala Ala Lys Leu Met Lys Thr Cys 980 985 990 Ser Ser Ser Asn Lys Lys Leu Pro Ser Asp Glu Pro Lys Ser Ser Cys 995 1000 1005 Ile Leu Gln Ile Thr Val Glu Glu Phe His His Val Phe Arg Arg Ile 1010 1015 1020 Ala Asp Leu Gln Ser Pro Leu Phe Arg Gly Pro Asp Asp Asp Pro Ala 1025 1030 1035 1040 Ala Leu Phe Glu Met Ala Lys Ser Gly Gln Ser Lys Lys Pro Ser Asp 1045 1050 1055 Glu Leu Ser Gln Lys Thr Val Glu Cys Thr Thr Trp Leu Leu Cys Thr 1060 1065 1070 Cys Met Asp Thr Gly Glu Ala Leu Lys Phe Ser Leu Ser Glu Ser Gly 1075 1080 1085 Arg Arg Leu Gly Leu Val Pro Cys Gly Ala Val Gly Val Gln Leu Ser 1090 1095 1100 Glu Ile Gln Asp Gln Lys Trp Thr Val Lys Pro His Ile Gly Glu Val 1105 1110 1115 1120 Phe Cys Tyr Leu Pro Leu Arg Ile Lys Thr Gly Leu Pro Val His Ile 1125 1130 1135 Asn Gly Cys Phe Ala Val Thr Ser Asn Arg Lys Glu Ile Trp Lys Thr 1140 1145 1150 Asp Thr Lys Gly Arg Trp Asn Thr Thr Phe Met Arg His Val Ile Val 1155 1160 1165 Lys Ala Tyr Leu Gln Val Leu Ser Val Leu Arg Asp Leu Ala Thr Ser 1170 1175 1180 Gly Glu Leu Met Asp Tyr Thr Tyr Tyr Ala Val Trp Pro Asp Pro Asp 1185 1190 1195 1200 Leu Val His Asp Asp Phe Ser Val Ile Cys Gln Gly Phe Tyr Glu Asp 1205 1210 1215 Ile Ala His Gly Lys Gly Lys Glu Leu Thr Lys Val Phe Ser Asp Gly 1220 1225 1230 Ser Thr Trp Val Ser Met Lys Asn Val Arg Phe Leu Asp Asp Ser Ile 1235 1240 1245 Leu Lys Arg Arg Asp Val Gly Ser Ala Ala Phe Lys Ile Phe Leu Lys 1250 1255 1260 Tyr Leu Lys Lys Thr Gly Ser Lys Asn Leu Cys Ala Val Glu Leu Pro 1265 1270 1275 1280 Ser Ser Val Lys Leu Gly Phe Glu Glu Ala Gly Cys Lys Gln Ile Leu 1285 1290 1295 Leu Glu Asn Thr Phe Ser Glu Lys Gln Phe Phe Ser Glu Val Phe Phe 1300 1305 1310 Pro Asn Ile Gln Glu Ile Glu Ala Glu Leu Arg Asp Pro Leu Met Ile 1315 1320 1325 Phe Val Leu Asn Glu Lys Val Asp Glu Phe Ser Gly Val Leu Arg Val 1330 1335 1340 Thr Pro Cys Ile Pro Cys Ser Leu Glu Gly His Pro Leu Val Leu Pro 1345 1350 1355 1360 Ser Arg Leu Ile His Pro Glu Gly Arg Val Ala Lys Leu Phe Asp Ile 1365 1370 1375 Lys Asp Gly Arg Phe Pro Tyr Gly Ser Thr Gln Asp Tyr Leu Asn Pro 1380 1385 1390 Ile Ile Leu Ile Lys Leu Val Gln Leu Gly Met Ala Lys Asp Asp Ile 1395 1400 1405 Leu Trp Asp Asp Met Leu Glu Arg Ala Val Ser Val Ala Glu Ile Asn 1410 1415 1420 Lys Ser Asp His Val Ala Ala Cys Leu Arg Ser Ser Ile Leu Leu Ser 1425 1430 1435 1440 Leu Ile Asp Glu Lys Leu Lys Ile Arg Asp Pro Arg Ala Lys Asp Phe 1445 1450 1455 Ala Ala Lys Tyr Gln Thr Ile Arg Phe Leu Pro Phe Leu Thr Lys Pro 1460 1465 1470 Ala Gly Phe Ser Leu Asp Trp Lys Gly Asn Ser Phe Lys Pro Glu Thr 1475 1480 1485 Met Phe Ala Ala Thr Asp Leu Tyr Thr Ala Glu His Gln Asp Ile Val 1490 1495 1500 Cys Leu Leu Gln Pro Ile Leu Asn Glu Asn Ser His Ser Phe Arg Gly 1505 1510 1515 1520 Cys Gly Ser Val Ser Leu Ala Val Lys Glu Phe Leu Gly Leu Leu Lys 1525 1530 1535 Lys Pro Thr Val Asp Leu Val Ile Asn Gln Leu Lys Glu Val Ala Lys 1540 1545 1550 Ser Val Asp Asp Gly Ile Thr Leu Tyr Gln Glu Asn Ile Thr Asn Ala 1555 1560 1565 Cys Tyr Lys Tyr Leu His Glu Ala Leu Met Gln Asn Glu Ile Thr Lys 1570 1575 1580 Met Ser Ile Ile Asp Lys Leu Lys Pro Phe Ser Phe Ile Leu Val Glu 1585 1590 1595 1600 Asn Ala Tyr Val Asp Ser Glu Lys Val Ser Phe His Leu Asn Phe Glu 1605 1610 1615 Ala Ala Pro Tyr Leu Tyr Gln Leu Pro Asn Lys Tyr Lys Asn Asn Phe 1620 1625 1630 Arg Glu Leu Phe Glu Thr Val Gly Val Arg Gln Ser Cys Thr Val Glu 1635 1640 1645 Asp Phe Ala Leu Val Leu Glu Ser Ile Asp Gln Glu Arg Gly Thr Lys 1650 1655 1660 Gln Ile Thr Glu Glu Asn Phe Gln Leu Cys Arg Arg Ile Ile Ser Glu 1665 1670 1675 1680 Gly Ile Trp Ser Leu Ile Arg Glu Lys Lys Gln Glu Phe Cys Glu Lys 1685 1690 1695 Asn Tyr Gly Lys Ile Leu Leu Pro Asp Thr Asn Leu Met Leu Leu Pro 1700 1705 1710 Ala Lys Ser Leu Cys Tyr Asn Asp Cys Pro Trp Ile Lys Val Lys Asp 1715 1720 1725 Thr Thr Val Lys Tyr Cys His Ala Asp Ile Pro Arg Glu Val Ala Val 1730 1735 1740 Lys Leu Gly Ala Val Pro Lys Arg His Lys Ala Leu Glu Arg Tyr Ala 1745 1750 1755 1760 Ser Asn Val Cys Phe Thr Thr Leu Gly Thr Glu Phe Gly Gln Lys Glu 1765 1770 1775 Lys Leu Thr Ser Arg Ile Lys Ser Ile Leu Asn Ala Tyr Pro Ser Glu 1780 1785 1790 Lys Glu Met Leu Lys Glu Leu Leu Gln Asn Ala Asp Asp Ala Lys Ala 1795 1800 1805 Thr Glu Ile Cys Phe Val Phe Asp Pro Arg Gln His Pro Val Asp Arg 1810 1815 1820 Ile Phe Asp Asp Lys Trp Ala Pro Leu Gln Gly Pro Ala Leu Cys Val 1825 1830 1835 1840 Tyr Asn Asn Gln Pro Phe Thr Glu Asp Asp Val Arg Gly Ile Gln Asn 1845 1850 1855 Leu Gly Lys Gly Thr Lys Glu Gly Asn Pro Tyr Lys Thr Gly Gln Tyr 1860 1865 1870 Gly Ile Gly Phe Asn Ser Val Tyr His Ile Thr Asp Cys Pro Ser Phe 1875 1880 1885 Ile Ser Gly Asn Asp Ile Leu Cys Ile Phe Asp Pro His Ala Arg Tyr 1890 1895 1900 Ala Pro Gly Ala Thr Ser Ile Ser Pro Gly Arg Met Phe Arg Asp Leu 1905 1910 1915 1920 Asp Ala Asp Phe Arg Thr Gln Phe Ser Asp Val Leu Asp Leu Tyr Leu 1925 1930 1935 Gly Thr His Phe Lys Leu Asp Asn Cys Thr Met Phe Arg Phe Pro Leu 1940 1945 1950 Arg Asn Ala Glu Met Ala Lys Val Ser Glu Ile Ser Ser Val Pro Ala 1955 1960 1965 Ser Asp Arg Met Val Gln Asn Leu Leu Asp Lys Leu Arg Ser Asp Gly 1970 1975 1980 Ala Glu Leu Leu Met Phe Leu Asn His Met Glu Lys Ile Ser Ile Cys 1985 1990 1995 2000 Glu Ile Asp Lys Ser Thr Gly Ala Leu Asn Val Leu Tyr Ser Val Lys 2005 2010 2015 Gly Lys Ile Thr Asp Gly Asp Arg Leu Lys Arg Lys Gln Phe His Ala 2020 2025 2030 Ser Val Ile Asp Ser Val Thr Lys Lys Arg Gln Leu Lys Asp Ile Pro 2035 2040 2045 Val Gln Gln Ile Thr Tyr Thr Met Asp Thr Glu Asp Ser Glu Gly Asn 2050 2055 2060 Leu Thr Thr Trp Leu Ile Cys Asn Arg Ser Gly Phe Ser Ser Met Glu 2065 2070 2075 2080 Lys Val Ser Lys Ser Val Ile Ser Ala His Lys Asn Gln Asp Ile Thr 2085 2090 2095 Leu Phe Pro Arg Gly Gly Val Ala Ala Cys Ile Thr His Asn Tyr Lys 2100 2105 2110 Lys Pro His Arg Ala Phe Cys Phe Leu Pro Leu Ser Leu Glu Thr Gly 2115 2120 2125 Leu Pro Phe His Val Asn Gly His Phe Ala Leu Asp Ser Ala Arg Arg 2130 2135 2140 Asn Leu Trp Arg Asp Asp Asn Gly Val Gly Val Arg Ser Asp Trp Asn 2145 2150 2155 2160 Asn Ser Leu Met Thr Ala Leu Ile Ala Pro Ala Tyr Val Glu Leu Leu 2165 2170 2175 Ile Gln Leu Lys Lys Arg Tyr Phe Pro Gly Ser Asp Pro Thr Leu Ser 2180 2185 2190 Val Leu Gln Asn Thr Pro Ile His Val Val Lys Asp Thr Leu Lys Lys 2195 2200 2205 Phe Leu Ser Phe Phe Pro Val Asn Arg Leu Asp Leu Gln Pro Asp Leu 2210 2215 2220 Tyr Cys Leu Val Lys Ala Leu Tyr Asn Cys Ile His Glu Asp Met Lys 2225 2230 2235 2240 Arg Leu Leu Pro Val Val Arg Ala Pro Asn Ile Asp Gly Ser Asp Leu 2245 2250 2255 His Ser Ala Val Ile Ile Thr Trp Ile Asn Met Ser Thr Ser Asn Lys 2260 2265 2270 Thr Arg Pro Phe Phe Asp Asn Leu Leu Gln Asp Glu Leu Gln His Leu 2275 2280 2285 Lys Asn Ala Asp Tyr Asn Ile Thr Thr Arg Lys Thr Val Ala Glu Asn 2290 2295 2300 Val Tyr Arg Leu Lys His Leu Leu Leu Glu Ile Gly Phe Asn Leu Val 2305 2310 2315 2320 Tyr Asn Cys Asp Glu Thr Ala Asn Leu Tyr His Cys Leu Ile Asp Ala 2325 2330 2335 Asp Ile Pro Val Ser Tyr Val Thr Pro Ala Asp Ile Arg Ser Phe Leu 2340 2345 2350 Met Thr Phe Ser Ser Pro Asp Thr Asn Cys His Ile Gly Lys Leu Pro 2355 2360 2365 Cys Arg Leu Gln Gln Thr Asn Leu Lys Leu Phe His Ser Leu Lys Leu 2370 2375 2380 Leu Val Asp Tyr Cys Phe Lys Asp Ala Glu Glu Asn Glu Ile Glu Val 2385 2390 2395 2400 Glu Gly Leu Pro Leu Leu Ile Thr Leu Asp Ser Val Leu Gln Thr Phe 2405 2410 2415 Asp Ala Lys Arg Pro Lys Phe Leu Thr Thr Tyr His Glu Leu Ile Pro 2420 2425 2430 Ser Arg Lys Asp Leu Phe Met Asn Thr Leu Tyr Leu Lys Tyr Ser Asn 2435 2440 2445 Ile Leu Leu Asn Cys Lys Val Ala Lys Val Phe Asp Ile Ser Ser Phe 2450 2455 2460 Ala Asp Leu Leu Ser Ser Val Leu Pro Arg Glu Tyr Lys Thr Lys Ser 2465 2470 2475 2480 Cys Thr Lys Trp Lys Asp Asn Phe Ala Ser Glu Ser Trp Leu Lys Asn 2485 2490 2495 Ala Trp His Phe Ile Ser Glu Ser Val Ser Val Lys Glu Asp Gln Glu 2500 2505 2510 Glu Thr Lys Pro Thr Phe Asp Ile Val Val Asp Thr Leu Lys Asp Trp 2515 2520 2525 Ala Leu Leu Pro Gly Thr Lys Phe Thr Val Ser Ala Asn Gln Leu Val 2530 2535 2540 Val Pro Glu Gly Asp Val Leu Leu Pro Leu Ser Leu Met His Ile Ala 2545 2550 2555 2560 Val Phe Pro Asn Ala Gln Ser Asp Lys Val Phe His Ala Leu Met Lys 2565 2570 2575 Ala Gly Cys Ile Gln Leu Ala Leu Asn Lys Ile Cys Ser Lys Asp Ser 2580 2585 2590 Ala Leu Val Pro Leu Leu Ser Cys His Thr Ala Asn Ile Glu Ser Pro 2595 2600 2605 Thr Ser Ile Leu Lys Ala Leu His Tyr Met Val Gln Thr Ser Thr Phe 2610 2615 2620 Arg Ala Glu Lys Leu Val Glu Asn Asp Phe Glu Ala Leu Leu Met Tyr 2625 2630 2635 2640 Phe Asn Cys Asn Leu Asn His Leu Met Ser Gln Asp Asp Ile Lys Ile 2645 2650 2655 Leu Lys Ser Leu Pro Cys Tyr Lys Ser Ile Ser Gly Arg Tyr Val Ser 2660 2665 2670 Ile Gly Lys Phe Gly Thr Cys Tyr Val Leu Thr Lys Ser Ile Pro Ser 2675 2680 2685 Ala Glu Val Glu Lys Trp Thr Gln Ser Ser Ser Ser Ala Phe Leu Glu 2690 2695 2700 Glu Lys Ile His Leu Lys Glu Leu Tyr Glu Val Ile Gly Cys Val Pro 2705 2710 2715 2720 Val Asp Asp Leu Glu Val Tyr Leu Lys His Leu Leu Pro Lys Ile Glu 2725 2730 2735 Asn Leu Ser Tyr Asp Ala Lys Leu Glu His Leu Ile Tyr Leu Lys Asn 2740 2745 2750 Arg Leu Ser Ser Ala Glu Glu Leu Ser Glu Ile Lys Glu Gln Leu Phe 2755 2760 2765 Glu Lys Leu Glu Ser Leu Leu Ile Ile His Asp Ala Asn Ser Arg Leu 2770 2775 2780 Lys Gln Ala Lys His Phe Tyr Asp Arg Thr Val Arg Val Phe Glu Val 2785 2790 2795 2800 Met Leu Pro Glu Lys Leu Phe Ile Pro Asn Asp Phe Phe Lys Lys Leu 2805 2810 2815 Glu Gln Leu Ile Lys Pro Lys Asn His Val Thr Phe Met Thr Ser Trp 2820 2825 2830 Val Glu Phe Leu Arg Asn Ile Gly Leu Lys Tyr Ile Leu Ser Gln Gln 2835 2840 2845 Gln Leu Leu Gln Phe Ala Lys Glu Ile Ser Val Arg Ala Asn Thr Glu 2850 2855 2860 Asn Trp Ser Lys Glu Thr Leu Gln Asn Thr Val Asp Ile Leu Leu His 2865 2870 2875 2880 His Ile Phe Gln Glu Arg Met Asp Leu Leu Ser Gly Asn Phe Leu Lys 2885 2890 2895 Glu Leu Ser Leu Ile Pro Phe Leu Cys Pro Glu Arg Ala Pro Ala Glu 2900 2905 2910 Phe Ile Arg Phe His Pro Gln Tyr Gln Glu Val Asn Gly Thr Leu Pro 2915 2920 2925 Leu Ile Lys Phe Asn Gly Ala Gln Val Asn Pro Lys Phe Lys Gln Cys 2930 2935 2940 Asp Val Leu Gln Leu Leu Trp Thr Ser Cys Pro Ile Leu Pro Glu Lys 2945 2950 2955 2960 Ala Thr Pro Leu Ser Ile Lys Glu Gln Glu Gly Ser Asp Leu Gly Pro 2965 2970 2975 Gln Glu Gln Leu Glu Gln Val Leu Asn Met Leu Asn Val Asn Leu Asp 2980 2985 2990 Pro Pro Leu Asp Lys Val Ile Asn Asn Cys Arg Asn Ile Cys Asn Ile 2995 3000 3005 Thr Thr Leu Asp Glu Glu Met Val Lys Thr Arg Ala Lys Val Leu Arg 3010 3015 3020 Ser Ile Tyr Glu Phe Leu Ser Ala Glu Lys Arg Glu Phe Arg Phe Gln 3025 3030 3035 3040 Leu Arg Gly Val Ala Phe Val Met Val Glu Asp Gly Trp Lys Leu Leu 3045 3050 3055 Lys Pro Glu Glu Val Val Ile Asn Leu Glu Tyr Glu Ser Asp Phe Lys 3060 3065 3070 Pro Tyr Leu Tyr Lys Leu Pro Leu Glu Leu Gly Thr Phe His Gln Leu 3075 3080 3085 Phe Lys His Leu Gly Thr Glu Asp Ile Ile Ser Thr Lys Gln Tyr Val 3090 3095 3100 Glu Val Leu Ser Arg Ile Phe Lys Asn Ser Glu Gly Lys Gln Leu Asp 3105 3110 3115 3120 Pro Asn Glu Met Arg Thr Val Lys Arg Val Val Ser Gly Leu Phe Arg 3125 3130 3135 Ser Leu Gln Asn Asp Ser Val Lys Val Arg Ser Asp Leu Glu Asn Val 3140 3145 3150 Arg Asp Leu Ala Leu Tyr Leu Pro Ser Gln Asp Gly Arg Leu Val Lys 3155 3160 3165 Ser Ser Ile Leu Val Phe Asp Asp Ala Pro His Tyr Lys Ser Arg Ile 3170 3175 3180 Gln Gly Asn Ile Gly Val Gln Met Leu Val Asp Leu Ser Gln Cys Tyr 3185 3190 3195 3200 Leu Gly Lys Asp His Gly Phe His Thr Lys Leu Ile Met Leu Phe Pro 3205 3210 3215 Gln Lys Leu Arg Pro Arg Leu Leu Ser Ser Ile Leu Glu Glu Gln Leu 3220 3225 3230 Asp Glu Glu Thr Pro Lys Val Cys Gln Phe Gly Ala Leu Cys Ser Leu 3235 3240 3245 Gln Gly Arg Leu Gln Leu Leu Leu Ser Ser Glu Gln Phe Ile Thr Gly 3250 3255 3260 Leu Ile Arg Ile Met Lys His Glu Asn Asp Asn Ala Phe Leu Ala Asn 3265 3270 3275 3280 Glu Glu Lys Ala Ile Arg Leu Cys Lys Ala Leu Arg Glu Gly Leu Lys 3285 3290 3295 Val Ser Cys Phe Glu Lys Leu Gln Thr Thr Leu Arg Val Lys Gly Phe 3300 3305 3310 Asn Pro Ile Pro His Ser Arg Ser Glu Thr Phe Ala Phe Leu Lys Arg 3315 3320 3325 Phe Gly Asn Ala Val Ile Leu Leu Tyr Ile Gln His Ser Asp Ser Lys 3330 3335 3340 Asp Ile Asn Phe Leu Leu Ala Leu Ala Met Thr Leu Lys Ser Ala Thr 3345 3350 3355 3360 Asp Asn Leu Ile Ser Asp Thr Ser Tyr Leu Ile Ala Met Leu Gly Cys 3365 3370 3375 Asn Asp Ile Tyr Arg Ile Gly Glu Lys Leu Asp Ser Leu Gly Val Lys 3380 3385 3390 Tyr Asp Ser Ser Glu Pro Ser Lys Leu Glu Leu Pro Met Pro Gly Thr 3395 3400 3405 Pro Ile Pro Ala Glu Ile His Tyr Thr Leu Leu Met Asp Pro Met Asn 3410 3415 3420 Val Phe Tyr Pro Gly Glu Tyr Val Gly Tyr Leu Val Asp Ala Glu Gly 3425 3430 3435 3440 Gly Asp Ile Tyr Gly Ser Tyr Gln Pro Thr Tyr Thr Tyr Ala Ile Ile 3445 3450 3455 Val Gln Glu Val Glu Arg Glu Asp Ala Asp Asn Ser Ser Phe Leu Gly 3460 3465 3470 Lys Ile Tyr Gln Ile Asp Ile Gly Tyr Ser Glu Tyr Lys Ile Val Ser 3475 3480 3485 Ser Leu Asp Leu Tyr Lys Phe Ser Arg Pro Glu Glu Ser Ser Gln Ser 3490 3495 3500 Arg Asp Ser Ala Pro Ser Thr Pro Thr Ser Pro Thr Glu Phe Leu Thr 3505 3510 3515 3520 Pro Gly Leu Arg Ser Ile Pro Pro Leu Phe Ser Gly Arg Glu Ser His 3525 3530 3535 Lys Thr Ser Ser Lys His Gln Ser Pro Lys Lys Leu Lys Val Asn Ser 3540 3545 3550 Leu Pro Glu Ile Leu Lys Glu Val Thr Ser Val Val Glu Gln Ala Trp 3555 3560 3565 Lys Leu Pro Glu Ser Glu Arg Lys Lys Ile Ile Arg Arg Leu Tyr Leu 3570 3575 3580 Lys Trp His Pro Asp Lys Asn Pro Glu Asn His Asp Ile Ala Asn Glu 3585 3590 3595 3600 Val Phe Lys His Leu Gln Asn Glu Ile Asn Arg Leu Glu Lys Gln Ala 3605 3610 3615 Phe Leu Asp Gln Asn Ala Asp Arg Ala Ser Arg Arg Thr Phe Ser Thr 3620 3625 3630 Ser Ala Ser Arg Phe Gln Ser Asp Lys Tyr Ser Phe Gln Arg Phe Tyr 3635 3640 3645 Thr Ser Trp Asn Gln Glu Ala Thr Ser His Lys Ser Glu Arg Gln Gln 3650 3655 3660 Gln Asn Lys Glu Lys Cys Pro Pro Ser Ala Gly Gln Thr Tyr Ser Gln 3665 3670 3675 3680 Arg Phe Phe Val Pro Pro Thr Phe Lys Ser Val Gly Asn Pro Val Glu 3685 3690 3695 Ala Arg Arg Trp Leu Arg Gln Ala Arg Ala Asn Phe Ser Ala Ala Arg 3700 3705 3710 Asn Asp Leu His Lys Asn Ala Asn Glu Trp Val Cys Phe Lys Cys Tyr 3715 3720 3725 Leu Ser Thr Lys Leu Ala Leu Ile Ala Ala Asp Tyr Ala Val Arg Gly 3730 3735 3740 Lys Ser Asp Lys Asp Val Lys Pro Thr Ala Leu Ala Gln Lys Ile Glu 3745 3750 3755 3760 Glu Tyr Ser Gln Gln Leu Glu Gly Leu Thr Asn Asp Val His Thr Leu 3765 3770 3775 Glu Ala Tyr Gly Val Asp Ser Leu Lys Thr Arg Tyr Pro Asp Leu Leu 3780 3785 3790 Pro Phe Pro Gln Ile Pro Asn Asp Arg Phe Thr Ser Glu Val Ala Met 3795 3800 3805 Arg Val Met Glu Cys Thr Ala Cys Ile Ile Ile Lys Leu Glu Asn Phe 3810 3815 3820 Met Gln Gln Lys Val 3825 <210> SEQ ID NO 17 <211> LENGTH: 11 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 17 acccctattc a 11 <210> SEQ ID NO 18 <211> LENGTH: 10 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 18 accccattca 10 <210> SEQ ID NO 19 <211> LENGTH: 10 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 19 aaagcgacac 10 <210> SEQ ID NO 20 <211> LENGTH: 10 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY: misc_feature <222> LOCATION: (1)...(10) <223> OTHER INFORMATION: n = A,T,C or G <400> SEQUENCE: 20 aaagngacac 10 <210> SEQ ID NO 21 <211> LENGTH: 26 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: oligonucleotide primer <400> SEQUENCE: 21 ccttccagta ctgtgttatt tgtgag 26 <210> SEQ ID NO 22 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: oligonucleotide primer <400> SEQUENCE: 22 caagaacttc ctcagggcat c 21 <210> SEQ ID NO 23 <211> LENGTH: 23 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: oligonucleotide primer <400> SEQUENCE: 23 gatgcatcta tacaacatcc gct 23 <210> SEQ ID NO 24 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: oligonucleotide primers <400> SEQUENCE: 24 gggtgggaaa taggttcctt c 21 <210> SEQ ID NO 25 <211> LENGTH: 23 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: oligonucleotide primers <400> SEQUENCE: 25 aaaaatgaga atccaaatgt gct 23 <210> SEQ ID NO 26 <211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: oligonucleotide primers <400> SEQUENCE: 26 gcactaaggc taggttttgt gaag 24 <210> SEQ ID NO 27 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: oligonucleotide primers <400> SEQUENCE: 27 gctcctcact tcctcttgtt g 21 <210> SEQ ID NO 28 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: oligonucleotide primers <400> SEQUENCE: 28 cgtgaattgg cttcatgata a 21 <210> SEQ ID NO 29 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: oligonucleotide primers <400> SEQUENCE: 29 agcaatcaga ttccagcaag c 21 <210> SEQ ID NO 30 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: oligonucleotide primers <400> SEQUENCE: 30 gatgggaatg tcagtgatat gg 22 <210> SEQ ID NO 31 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: oligonucleotide primers <400> SEQUENCE: 31 gggagaagtt gacaaagttg ga 22 <210> SEQ ID NO 32 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: oligonucleotide primers <400> SEQUENCE: 32 ctttggttca tcactgggaa g 21 <210> SEQ ID NO 33 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: oligonucleotide primers <400> SEQUENCE: 33 tccaaagcat tgaacacacc t 21 <210> SEQ ID NO 34 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: oligonucleotide primers <400> SEQUENCE: 34 caggtcccgt aagacactca g 21 <210> SEQ ID NO 35 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: oligonucleotide primers <400> SEQUENCE: 35 caatgggtgc tttgctgtta c 21 <210> SEQ ID NO 36 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: oligonucleotide primers <400> SEQUENCE: 36 cgaagaactc ccgagaactc a 21 <210> SEQ ID NO 37 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: oligonucleotide primers <400> SEQUENCE: 37 gctggctgca aacagatact ac 22 <210> SEQ ID NO 38 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: oligonucleotide primers <400> SEQUENCE: 38 gcaaacatgg tttcaggctt a 21 <210> SEQ ID NO 39 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: oligonucleotide primers <400> SEQUENCE: 39 caaacaatcc gcttccttcc at 22 <210> SEQ ID NO 40 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: oligonucleotide primers <400> SEQUENCE: 40 attattcgtc ggcaaagctg a 21 <210> SEQ ID NO 41 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: oligonucleotide primers <400> SEQUENCE: 41 ttccgcgaac tttttgaaac c 21 <210> SEQ ID NO 42 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: oligonucleotide primers <400> SEQUENCE: 42 acacaaagtg ctggcccttg c 21 <210> SEQ ID NO 43 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: oligonucleotide primers <400> SEQUENCE: 43 gatgcaaagg cgacagaaat c 21 <210> SEQ ID NO 44 <211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: oligonucleotide primers <400> SEQUENCE: 44 atacagcaca tttagagctc cagt 24 <210> SEQ ID NO 45 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: oligonucleotide primers <400> SEQUENCE: 45 gcatcagaca gaatggtcca g 21 <210> SEQ ID NO 46 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: oligonucleotide primers <400> SEQUENCE: 46 gcaattcaac atatgcagga g 21 <210> SEQ ID NO 47 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: oligonucleotide primers <400> SEQUENCE: 47 gtgaatggcc actttgcact 20 <210> SEQ ID NO 48 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: oligonucleotide primers <400> SEQUENCE: 48 tgatatcagc aggggtcaca t 21 <210> SEQ ID NO 49 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: oligonucleotide primers <400> SEQUENCE: 49 accacacgca aaacagtagc a 21 <210> SEQ ID NO 50 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: oligonucleotide primers <400> SEQUENCE: 50 gccatgcatt cttaagccaa g 21 <210> SEQ ID NO 51 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: oligonucleotide primers <400> SEQUENCE: 51 tgacatttcc agctttgctg a 21 <210> SEQ ID NO 52 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: oligonucleotide primers <400> SEQUENCE: 52 agcggccact gatggattta t 21 <210> SEQ ID NO 53 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: oligonucleotide primers <400> SEQUENCE: 53 aaatgatttt gaggcacttt tg 22 <210> SEQ ID NO 54 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: oligonucleotide primers <400> SEQUENCE: 54 ttccacccag gatgtcataa a 21 <210> SEQ ID NO 55 <211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: oligonucleotide primers <400> SEQUENCE: 55 acagtagact aaagcaagca aagc 24 <210> SEQ ID NO 56 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: oligonucleotide primers <400> SEQUENCE: 56 atcaagagga ggatccaggt t 21 <210> SEQ ID NO 57 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: oligonucleotide primers <400> SEQUENCE: 57 catcctgccc tattcttcca g 21 <210> SEQ ID NO 58 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: oligonucleotide primers <400> SEQUENCE: 58 taaagcgcaa ggtctcgtac a 21 <210> SEQ ID NO 59 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: oligonucleotide primers <400> SEQUENCE: 59 tgagggcaaa caattagatc c 21 <210> SEQ ID NO 60 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: oligonucleotide primers <400> SEQUENCE: 60 tctgctgtgg ggaataggat t 21 <210> SEQ ID NO 61 <211> LENGTH: 22 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: oligonucleotide primers <400> SEQUENCE: 61 gcaaagccct aagagaagga tt 22 <210> SEQ ID NO 62 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: oligonucleotide primers <400> SEQUENCE: 62 tgctttgaga gctttcctca g 21 <210> SEQ ID NO 63 <211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: oligonucleotide primers <400> SEQUENCE: 63 tgaaagagaa gatgctgaca attc 24 <210> SEQ ID NO 64 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: oligonucleotide primers <400> SEQUENCE: 64 gtaagtctgt ccggctgaag g 21 <210> SEQ ID NO 65 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: oligonucleotide primers <400> SEQUENCE: 65 catcccgatt tcagtcagac a 21 <210> SEQ ID NO 66 <211> LENGTH: 23 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: oligonucleotide primers <400> SEQUENCE: 66 ttcgtgctac aacacattca aga 23 <210> SEQ ID NO 67 <211> LENGTH: 129 <212> TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 67 Gly Gln Arg Glu Pro Leu Thr Val Arg Ile Lys Asn Ile Leu Glu Glu 1 5 10 15 Tyr Pro Ser Val Ser Asp Ile Phe Lys Glu Ile Leu Gln Asn Ala Asp 20 25 30 Asp Ala Asn Ala Thr Glu Cys Ser Phe Leu Ile Asp Met Arg Arg Asn 35 40 45 Met Asp Ile Arg Glu Asn Leu Leu Asp Pro Gly Met Ala Ala Cys His 50 55 60 Gly Pro Ala Leu Trp Ser Phe Asn Asn Ser Gln Phe Ser Asp Ser Asp 65 70 75 80 Phe Val Asn Ile Thr Arg Leu Gly Glu Ser Leu Lys Arg Gly Glu Val 85 90 95 Asp Lys Val Gly Lys Phe Gly Leu Gly Phe Asn Ser Val Tyr His Ile 100 105 110 Thr Asp Ile Pro Ile Ile Met Ser Arg Glu Phe Met Ile Met Phe Asp 115 120 125 Pro <210> SEQ ID NO 68 <400> SEQUENCE: 68 000 <210> SEQ ID NO 69 <400> SEQUENCE: 69 000 <210> SEQ ID NO 70 <400> SEQUENCE: 70 000 <210> SEQ ID NO 71 <400> SEQUENCE: 71 000 <210> SEQ ID NO 72 <211> LENGTH: 25 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: oligonucleotide primers <400> SEQUENCE: 72 tcattcatat gtcccaggga catgt 25 <210> SEQ ID NO 73 <211> LENGTH: 11 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: oligonucleotide primers <400> SEQUENCE: 73 acccctattc a 11 

What is claimed is:
 1. An isolated nucleic acid molecule comprising a nucleotide sequence of SEQ ID NO: 7 or the complement of SEQ ID NO:
 7. 2. A nucleic acid construct comprising the isolated nucleic acid molecule of claim
 1. 3. The nucleic acid construct of claim 2 wherein the isolated nucleic acid molecule is operatively linked to a regulatory sequence.
 4. A recombinant host cell comprising the isolated nucleic acid molecule of claim
 1. 5. The recombinant host cell of claim 4 wherein the isolated nucleic acid is operatively linked to a regulatory sequence.
 6. An isolated nucleic acid molecule consisting of a nucleotide sequence of SEQ ID NO: 47 or the complement of SEQ ID NO:
 47. 